//  DOQCS : http://doqcs.ncbs.res.in/ 
//  Accession Name = Synaptic_Network 
//  Accession Number = 16 
//  Transcriber = Upinder S. Bhalla, NCBS 
//  Developer = Upinder S. Bhalla, NCBS 
//  Species = Generic mammalian 
//  Tissue = Neuronal 
//  Cell Compartment = Synapse 
//  Notes = This model is an annotated version of the synaptic signaling network.<br>The primary reference is <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888852&dopt=Abstract">Bhalla US and Iyengar R. Science (1999) 283(5400):381-7</a> but several of the model pathways have been updated.<br><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12124261&query_hl=5">Bhalla US Biophys J. 2002 Aug;83(2):740-52</a><br><a href ="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12154335&query_hl=5">Bhalla US  J Comput Neurosci. 2002 Jul-Aug;13(1):49-62</a> 
 
 //genesis
// kkit Version 11 flat dumpfile
 
// Saved on Thu Dec  8 14:43:42 2005
 
include kkit {argv 1}
 
FASTDT = 0.0001
SIMDT = 0.001
CONTROLDT = 1
PLOTDT = 1
MAXTIME = 200
TRANSIENT_TIME = 2
VARIABLE_DT_FLAG = 1
DEFAULT_VOL = 1.6667e-21
VERSION = 11.0
setfield /file/modpath value /home2/bhalla/scripts/modules
kparms
 
//genesis

initdump -version 3 -ignoreorphans 1
simobjdump doqcsinfo filename accessname accesstype transcriber developer \
  citation species tissue cellcompartment methodology sources \
  model_implementation model_validation x y z
simobjdump table input output alloced step_mode stepsize x y z
simobjdump xtree path script namemode sizescale
simobjdump xcoredraw xmin xmax ymin ymax
simobjdump xtext editable
simobjdump xgraph xmin xmax ymin ymax overlay
simobjdump xplot pixflags script fg ysquish do_slope wy
simobjdump group xtree_fg_req xtree_textfg_req plotfield expanded movealone \
  link savename file version md5sum mod_save_flag x y z
simobjdump geometry size dim shape outside xtree_fg_req xtree_textfg_req x y \
  z
simobjdump kpool DiffConst CoInit Co n nInit mwt nMin vol slave_enable \
  geomname xtree_fg_req xtree_textfg_req x y z
simobjdump kreac kf kb notes xtree_fg_req xtree_textfg_req x y z
simobjdump kenz CoComplexInit CoComplex nComplexInit nComplex vol k1 k2 k3 \
  keepconc usecomplex notes xtree_fg_req xtree_textfg_req link x y z
simobjdump stim level1 width1 delay1 level2 width2 delay2 baselevel trig_time \
  trig_mode notes xtree_fg_req xtree_textfg_req is_running x y z
simobjdump xtab input output alloced step_mode stepsize notes editfunc \
  xtree_fg_req xtree_textfg_req baselevel last_x last_y is_running x y z
simobjdump kchan perm gmax Vm is_active use_nernst notes xtree_fg_req \
  xtree_textfg_req x y z
simobjdump transport input output alloced step_mode stepsize dt delay clock \
  kf xtree_fg_req xtree_textfg_req x y z
simobjdump proto x y z
simundump geometry /kinetics/geometry 0 1e-15 3 sphere "" white black 99 145 \
  0
simundump geometry /kinetics/geometry[1] 0 1.6667e-21 3 sphere "" white black \
  99 140 0
simundump geometry /kinetics/geometry[2] 0 1.6e-16 3 sphere "" white black 99 \
  135 0
simundump geometry /kinetics/geometry[3] 0 1e-13 3 sphere "" white black 99 \
  130 0
simundump geometry /kinetics/geometry[4] 0 1e-15 3 sphere "" white black 99 \
  125 0
simundump geometry /kinetics/geometry[5] 0 1.6e-16 3 sphere "" white black 99 \
  120 0
simundump geometry /kinetics/geometry[6] 0 1e-13 3 sphere "" white black 99 \
  115 0
simundump group /kinetics/PKC 0 blue black x 0 0 "" defaultfile \
  /home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 47 80 0
simundump kpool /kinetics/PKC/PKC-Ca 0 0 3.7208e-17 3.7208e-17 2.2325e-11 \
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simundump kreac /kinetics/PKC/PKC-act-by-Ca 0 1e-06 0.5 "" white blue 48 72 0
simundump kreac /kinetics/PKC/PKC-act-by-DAG 0 1.3333e-08 8.6348 "" white \
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simundump kreac /kinetics/PKC/PKC-Ca-to-memb 0 1.2705 3.5026 "" white blue 48 \
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simundump kreac /kinetics/PKC/PKC-DAG-to-memb 0 1 0.1 "" white blue 56 76 0
simundump kreac /kinetics/PKC/PKC-act-by-Ca-AA 0 2e-09 0.1 "" white blue 50 \
  76 0
simundump kreac /kinetics/PKC/PKC-act-by-DAG-AA 0 2 0.2 "" white blue 54 76 0
simundump kpool /kinetics/PKC/PKC-DAG-AA* 0 0 4.9137e-18 4.9137e-18 \
  2.9482e-12 2.9482e-12 0 0 6e+05 0 /kinetics/geometry[4] cyan blue 54 78 0
simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0 1.75e-16 1.75e-16 1.05e-10 \
  1.05e-10 0 0 6e+05 0 /kinetics/geometry[4] orange blue 50 78 0
simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0 1.3896e-17 1.3896e-17 \
  8.3376e-12 8.3376e-12 0 0 6e+05 0 /kinetics/geometry[4] pink blue 48 78 0
simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0 9.4352e-21 9.4352e-21 \
  5.6611e-15 5.6611e-15 0 0 6e+05 0 /kinetics/geometry[4] yellow blue 56 78 0
simundump kpool /kinetics/PKC/PKC-basal* 0 0 0.02 0.02 12000 12000 0 0 6e+05 \
  0 /kinetics/geometry[4] pink blue 46 78 0
simundump kreac /kinetics/PKC/PKC-basal-act 0 1 50 "" white blue 46 72 0
simundump kpool /kinetics/PKC/PKC-AA* 0 0 1.8133e-17 1.8133e-17 1.088e-11 \
  1.088e-11 0 0 6e+05 0 /kinetics/geometry[4] cyan blue 52 78 0
simundump kreac /kinetics/PKC/PKC-act-by-AA 0 2e-10 0.1 "" white blue 50 72 0
simundump kpool /kinetics/PKC/PKC-Ca-DAG 0 0 8.4632e-23 8.4632e-23 5.0779e-17 \
  5.0779e-17 0 0 6e+05 0 /kinetics/geometry[4] white blue 56 74 0
simundump kreac /kinetics/PKC/PKC-n-DAG 0 1e-09 0.1 "" white blue 52 72 0
simundump kpool /kinetics/PKC/PKC-DAG 0 0 1.161e-16 1.161e-16 6.9661e-11 \
  6.9661e-11 0 0 6e+05 0 /kinetics/geometry[4] white blue 52 74 0
simundump kreac /kinetics/PKC/PKC-n-DAG-AA 0 3e-08 2 "" white blue 54 72 0
simundump kpool /kinetics/PKC/PKC-DAG-AA 0 0 2.5188e-19 2.5188e-19 1.5113e-13 \
  1.5113e-13 0 0 6e+05 0 /kinetics/geometry[4] white blue 54 74 0
simundump kpool /kinetics/PKC/PKC-cytosolic 0 0 1 1 6e+05 6e+05 0 0 6e+05 0 \
  /kinetics/geometry[4] white blue 50 70 0
simundump kpool /kinetics/DAG 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  green black 5 -14 0
simundump kpool /kinetics/AA 0 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  darkgreen black 50 68 0
simundump kpool /kinetics/PKC-active 1 0 2.1222e-16 0.02 12000 12000 0 0 \
  6e+05 2 /kinetics/geometry[4] red black 52 80 0
simundump kenz /kinetics/PKC-active/PKC-act-raf 1 0 0 0 0 6e+05 5e-07 16 4 0 \
  0 "" red yellow "" 64 88 0
simundump kenz /kinetics/PKC-active/PKC-inact-GAP 1 0 0 0 0 1 1e-05 16 4 0 0 \
  "" red yellow "" 60 98 0
simundump kenz /kinetics/PKC-active/PKC-act-GEF 1 0 0 0 0 1 1e-05 16 4 0 0 "" \
  red yellow "" 64 98 0
simundump kenz /kinetics/PKC-active/PKC-phosph-neurogranin 1 0 0 0 0 6e+05 \
  1.7e-07 2.34 0.58 0 0 "" red red "" -55 -6 0
simundump kenz /kinetics/PKC-active/PKC-phosph-ng-CaM 1 0 0 0 0 6e+05 \
  1.02e-07 1.4 0.35 0 0 "" red red "" -59 -1 0
simundump kenz /kinetics/PKC-active/phosph-AC2 1 0 0 0 0 6e+05 1e-06 16 4 0 0 \
  "" red red "" -20 -31 0
simundump group /kinetics/PLA2 0 darkgreen black x 0 1 "" defaultfile \
  /home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 56 58 0
simundump kpool /kinetics/PLA2/PLA2-cytosolic 0 0 0.4 0.4 2.4e+05 2.4e+05 0 0 \
  6e+05 0 /kinetics/geometry[4] yellow darkgreen 48 57 0
simundump kreac /kinetics/PLA2/PLA2-Ca-act 0 1.6667e-06 0.1 "" white \
  darkgreen 51 62 0
simundump kpool /kinetics/PLA2/PLA2-Ca* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] yellow darkgreen 52 64 0
simundump kenz /kinetics/PLA2/PLA2-Ca*/kenz 0 0 0 0 0 6e+05 2.25e-06 21.6 5.4 \
  0 0 "" red yellow "" 52 66 0
simundump kreac /kinetics/PLA2/PIP2-PLA2-act 0 2e-09 0.5 "" white darkgreen \
  47 62 0
simundump kpool /kinetics/PLA2/PIP2-PLA2* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan darkgreen 46 64 0
simundump kenz /kinetics/PLA2/PIP2-PLA2*/kenz 0 0 0 0 0 6e+05 4.6e-06 44.16 \
  11.04 0 0 "" red cyan "" 46 66 0
simundump kreac /kinetics/PLA2/PIP2-Ca-PLA2-act 0 2e-08 0.1 "" white \
  darkgreen 49 62 0
simundump kpool /kinetics/PLA2/PIP2-Ca-PLA2* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan darkgreen 48 64 0
simundump kenz /kinetics/PLA2/PIP2-Ca-PLA2*/kenz 0 0 0 0 0 6e+05 1.5e-05 144 \
  36 0 0 "" red cyan "" 48 66 0
simundump kreac /kinetics/PLA2/DAG-Ca-PLA2-act 0 5e-09 4 "" white darkgreen \
  53 62 0
simundump kpool /kinetics/PLA2/DAG-Ca-PLA2* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] pink darkgreen 54 64 0
simundump kenz /kinetics/PLA2/DAG-Ca-PLA2*/kenz 0 0 0 0 0 6e+05 2.5e-05 240 \
  60 0 0 "" red pink "" 54 66 0
simundump kpool /kinetics/PLA2/APC 0 0 30 30 1.8e+07 1.8e+07 0 0 6e+05 5 \
  /kinetics/geometry[4] yellow darkgreen 50 64 0
simundump kreac /kinetics/PLA2/Degrade-AA 1 0.4 0 "" white darkgreen 50 66 0
simundump kpool /kinetics/PLA2/PLA2*-Ca 0 0 0 0 0 0 0 0 6e+05 1 \
  /kinetics/geometry[4] orange darkgreen 56 64 0
simundump kenz /kinetics/PLA2/PLA2*-Ca/kenz 0 0 0 0 0 6e+05 5e-05 480 120 0 0 \
  "" red orange "" 56 66 0
simundump kpool /kinetics/PLA2/PLA2* 1 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] orange darkgreen 56 60 0
simundump kreac /kinetics/PLA2/PLA2*-Ca-act 1 1e-05 0.1 "" white darkgreen 55 \
  62 0
simundump kreac /kinetics/PLA2/dephosphorylate-PLA2* 1 0.17 0 "" white \
  darkgreen 52 59 0
simundump kpool /kinetics/MAPK* 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  orange yellow 66 74 0
simundump kenz /kinetics/MAPK*/MAPK* 0 0 0 0 0 6e+05 6.5e-06 80 20 0 0 "" red \
  orange "" 51 57 0
simundump kenz /kinetics/MAPK*/MAPK*-feedback 1 0 0 0 0 6e+05 3.25e-06 40 10 \
  0 0 "" red orange "" 66 84 0
simundump kenz /kinetics/MAPK*/phosph_Sos 1 0 0 0 0 6e+05 3.25e-05 40 10 0 0 \
  "" red orange "" 72 111 0
simundump kpool /kinetics/temp-PIP2 1 0 2.5 2.5 1.5e+06 1.5e+06 0 0 6e+05 6 \
  /kinetics/geometry[4] green black 48 60 0
simundump kpool /kinetics/Glu 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  green black 14 -3 0
simundump group /kinetics/PLCbeta 1 maroon black x 0 1 "" defaultfile \
  /home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 5 -11 0
simundump kreac /kinetics/PLCbeta/Act-PLC-Ca 1 5e-06 1 "" white maroon 11 -16 \
  0
simundump kpool /kinetics/PLCbeta/PLC 1 0 0.8 0.8 4.8e+05 4.8e+05 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan maroon 12 -18 0
simundump kreac /kinetics/PLCbeta/Degrade-IP3 1 2.5 0 "" white maroon 9 -16 0
simundump kpool /kinetics/PLCbeta/Inositol 1 0 0 0 0 0 0 0 6e+05 4 \
  /kinetics/geometry[4] green maroon 9 -18 0
simundump kreac /kinetics/PLCbeta/Degrade-DAG 1 0.15 0 "" white maroon 3 -16 \
  0
simundump kpool /kinetics/PLCbeta/PC 1 0 0 0 0 0 0 0 1 4 /kinetics/geometry \
  green maroon 3 -18 0
simundump kpool /kinetics/PLCbeta/PLC-Ca 1 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan maroon 9 -14 0
simundump kenz /kinetics/PLCbeta/PLC-Ca/PLC-Ca 1 0 0 0 0 6e+05 4.2e-06 40 10 \
  0 0 "" red cyan "" 7 -16 0
simundump kreac /kinetics/PLCbeta/Act-PLC-by-Gq 1 4.2e-05 1 "" white maroon \
  11 9 0
simundump kreac /kinetics/PLCbeta/Inact-PLC-Gq 1 0.0133 0 "" white maroon 9 \
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simundump kpool /kinetics/PLCbeta/PLC-Ca-Gq 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan maroon 12 -10 0
simundump kenz /kinetics/PLCbeta/PLC-Ca-Gq/PLCb-Ca-Gq 0 0 0 0 0 6e+05 8e-05 \
  192 48 0 0 "" red cyan "" 5 -16 0
simundump kpool /kinetics/PLCbeta/PLC-Gq 1 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] cyan maroon 15 -14 0
simundump kreac /kinetics/PLCbeta/PLC-bind-Gq 1 4.2e-06 1 "" white maroon 13 \
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simundump kreac /kinetics/PLCbeta/PLC-Gq-bind-Ca 1 5e-05 1 "" white maroon 13 \
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simundump kpool /kinetics/BetaGamma 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/G*GTP 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  red black 5 -7 0
simundump kpool /kinetics/G*GDP 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry[4] \
  yellow black 2 -3 0
simundump group /kinetics/Gq 1 blue black x 0 1 "" defaultfile \
  /home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 6 1 0
simundump kreac /kinetics/Gq/RecLigandBinding 1 2.8e-05 10 "" white blue 8 -1 \
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simundump kpool /kinetics/Gq/G-GDP 1 0 1 1 6e+05 6e+05 0 0 6e+05 0 \
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simundump kreac /kinetics/Gq/Basal-Act-G 1 1e-04 0 "" white blue 4 -5 0
simundump kreac /kinetics/Gq/Trimerize-G 1 1e-05 0 "" white blue 3 -1 0
simundump kreac /kinetics/Gq/Inact-G 1 0.0133 0 "" white blue 2 -5 0
simundump kpool /kinetics/Gq/mGluR 1 0 0.3 0.3 1.8e+05 1.8e+05 0 0 6e+05 0 \
  /kinetics/geometry[4] green blue 8 1 0
simundump kpool /kinetics/Gq/Rec-Glu 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/Gq/Rec-Gq 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kreac /kinetics/Gq/Rec-Glu-bind-Gq 1 1e-08 1e-04 "" white blue 8 -5 \
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simundump kreac /kinetics/Gq/Glu-bind-Rec-Gq 1 2.8e-05 0.1 "" white blue 11 \
  -5 0
simundump kpool /kinetics/Gq/Rec-Glu-Gq 1 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry[4] orange blue 8 -7 0
simundump kreac /kinetics/Gq/Activate-Gq 1 0.01 0 "" white blue 6 -5 0
simundump kreac /kinetics/Gq/Rec-bind-Gq 1 1e-06 1 "" white blue 11 -1 0
simundump kpool /kinetics/Gq/mGluRAntag 1 0 0 0 0 0 0 0 6e+05 4 \
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simundump kreac /kinetics/Gq/Antag-bind-Rec-Gq 1 1e-04 0.01 "" white blue 14 \
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simundump kpool /kinetics/Gq/Blocked-rec-Gq 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump group /kinetics/MAPK 0 brown black x 0 1 "" defaultfile \
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simundump kpool /kinetics/MAPK/craf-1 0 0 0.2 0.2 1.2e+05 1.2e+05 0 0 6e+05 0 \
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simundump kpool /kinetics/MAPK/craf-1* 0 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/MAPK/MAPKK 0 0 0.18 0.18 1.08e+05 1.08e+05 0 0 \
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simundump kpool /kinetics/MAPK/MAPK 0 0 0.36 0.36 2.16e+05 2.16e+05 0 0 6e+05 \
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simundump kpool /kinetics/MAPK/craf-1** 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/MAPK/MAPK-tyr 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/MAPK/MAPKK* 0 0 0 0 0 0 0 0 6e+05 0 \
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simundump kenz /kinetics/MAPK/MAPKK*/MAPKKtyr 0 0 0 0 0 6e+05 2.7e-05 0.6 \
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simundump kenz /kinetics/MAPK/MAPKK*/MAPKKthr 1 0 0 0 0 6e+05 2.7e-05 0.6 \
  0.15 0 0 "" red pink "" 64 75 0
simundump kpool /kinetics/MAPK/MAPKK-ser 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/MAPK/Raf-GTP-Ras* 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kenz /kinetics/MAPK/Raf-GTP-Ras*/Raf-GTP-Ras*.1 1 0 0 0 0 1 5.5e-06 \
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simundump kenz /kinetics/MAPK/Raf-GTP-Ras*/Raf-GTP-Ras*.2 1 0 0 0 0 1 5.5e-06 \
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simundump kpool /kinetics/MKP-1 1 0 0.0032 0.0032 1920 1920 0 0 6e+05 0 \
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simundump kenz /kinetics/MKP-1/MKP1-tyr-deph 1 0 0 0 0 6e+05 0.000125 4 1 0 0 \
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simundump kenz /kinetics/MKP-1/MKP1-thr-deph 1 0 0 0 0 6e+05 0.000125 4 1 0 0 \
  "" red hotpink "" 68 75 0
simundump kreac /kinetics/Ras-act-craf 1 4e-05 0.5 "" white black 62 88 0
simundump kpool /kinetics/PPhosphatase2A 1 0 0.224 0.224 1.344e+05 1.344e+05 \
  0 0 6e+05 0 /kinetics/geometry[4] hotpink yellow 66 80 0
simundump kenz /kinetics/PPhosphatase2A/craf-deph 1 0 0 0 0 6e+05 3.3e-06 25 \
  6 0 0 "" red hotpink "" 64 84 0
simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph 1 0 0 0 0 6e+05 3.3e-06 25 \
  6 0 0 "" red hotpink "" 66 79 0
simundump kenz /kinetics/PPhosphatase2A/MAPKK-deph-ser 1 0 0 0 0 6e+05 \
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simundump kenz /kinetics/PPhosphatase2A/craf**-deph 1 0 0 0 0 1 3.3e-06 25 6 \
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simundump group /kinetics/Ras 1 blue black x 0 0 "" defaultfile defaultfile.g \
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simundump kreac /kinetics/Ras/bg-act-GEF 1 1e-05 1 "" white blue 68 98 0
simundump kpool /kinetics/Ras/GEF-Gprot-bg 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kenz /kinetics/Ras/GEF-Gprot-bg/GEF-bg_act-ras 1 0 0 0 0 6e+05 \
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simundump kreac /kinetics/Ras/dephosph-GEF 1 1 0 "" white blue 66 98 0
simundump kpool /kinetics/Ras/inact-GEF 1 0 0.1 0.1 60000 60000 0 0 6e+05 0 \
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simundump kpool /kinetics/Ras/GEF* 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kenz /kinetics/Ras/GEF*/GEF*-act-ras 1 0 0 0 0 6e+05 3.3e-07 0.08 \
  0.02 0 0 "" red hotpink "" 67 94 0
simundump kpool /kinetics/Ras/GTP-Ras 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/Ras/GDP-Ras 1 0 0.2 0.2 1.2e+05 1.2e+05 0 0 6e+05 0 \
  /kinetics/geometry[4] pink blue 64 96 0
simundump kreac /kinetics/Ras/Ras-intrinsic-GTPase 1 1e-04 0 "" white blue 63 \
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simundump kreac /kinetics/Ras/dephosph-GAP 1 0.1 0 "" white blue 62 98 0
simundump kpool /kinetics/Ras/GAP* 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kpool /kinetics/Ras/GAP 1 0 0.002 0.002 1200 1200 0 0 6e+05 0 \
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simundump kenz /kinetics/Ras/GAP/GAP-inact-ras 1 0 0 0 0 6e+05 0.001666 1000 \
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simundump kpool /kinetics/Ras/inact-GEF* 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kreac /kinetics/Ras/CaM-bind-GEF 1 1e-04 1 "" white blue 70 98 0
simundump kpool /kinetics/Ras/CaM-GEF 1 0 0 0 0 0 0 0 6e+05 0 \
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simundump kenz /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras 1 0 0 0 0 6e+05 3.3e-07 \
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simundump kreac /kinetics/Ras/dephosph-inact-GEF* 1 1 0 "" white blue 66 101 \
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simundump kpool /kinetics/PKA-active 1 0 0 0 0 0 0 0 6e+05 0 \
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loadtab -continue \
 0.08
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simundump doqcsinfo /kinetics/doqcsinfo 0 db16.g Synaptic_Network network \
  " Upinder S. Bhalla, NCBS" " Upinder S. Bhalla, NCBS" " " \
  "General Mammalian" Neuronal Synapse \
  "Quantitative match to experiments, Qualitative" \
  "<a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888852&dopt=Abstract>Bhalla US and Iyengar R. Science (1999) 283(5400):381-7</a> ( peer-reviewed publication )." \
  "Exact GENESIS implementation" \
  "Approximates original data,Quantitatively predicts new data " 99 150 0
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xtextload /file/notes \
"Merged in Ca13a.g into decode_ca_reg.g." \
"Minor cosmetic changes with positioning" \
"of molecules."
addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/PKC-Ca REAC B A 
addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/PKC/PKC-Ca REAC A B 
addmsg /kinetics/PKC/PKC-Ca-to-memb /kinetics/PKC/PKC-Ca REAC A B 
addmsg /kinetics/PKC/PKC-act-by-Ca-AA /kinetics/PKC/PKC-Ca REAC A B 
addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-act-by-Ca SUBSTRATE n 
addmsg /kinetics/Ca /kinetics/PKC/PKC-act-by-Ca SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-Ca PRODUCT n 
addmsg /kinetics/DAG /kinetics/PKC/PKC-act-by-DAG SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-DAG SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca-DAG /kinetics/PKC/PKC-act-by-DAG PRODUCT n 
addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-Ca-to-memb SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC/PKC-Ca-to-memb PRODUCT n 
addmsg /kinetics/PKC/PKC-Ca-DAG /kinetics/PKC/PKC-DAG-to-memb SUBSTRATE n 
addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC/PKC-DAG-to-memb PRODUCT n 
addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-Ca-AA SUBSTRATE n 
addmsg /kinetics/AA /kinetics/PKC/PKC-act-by-Ca-AA SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca-AA* /kinetics/PKC/PKC-act-by-Ca-AA PRODUCT n 
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addmsg /kinetics/PKC/PKC-DAG-AA /kinetics/PKC/PKC-act-by-DAG-AA SUBSTRATE n 
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addmsg /kinetics/Glu /graphs/conc1/Glu.Co PLOT Co *Glu.Co *green 
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enddump
// End of dump

setfield /kinetics/Ca_tab table->dx 0.1
setfield /kinetics/Ca_tab table->invdx 10
call /kinetics/PKC/notes LOAD \
"Protein Kinase C. This module represents a weighted average of" \
"the alpha, beta and gamma isoforms. It takes inputs from" \
"Ca, DAG (Diacyl Glycerol) and AA (arachidonic acid)." \
"Regulation parameters are largely from Schaechter and Benowitz" \
"1993 J Neurosci 13(10):4361 who use synaptosomes from" \
"mammalian brain and in one paper look at all three inputs." \
"Shinomura et al 1991 PNAS 88:5149-5153 is also a useful source" \
"of data and helps to tighten the DAG inputs. " \
"General reviews include Azzi et al 1992 Eur J Bioch 208:541" \
"and Nishizuka 1988, Nature 334:661" \
"Concentration info from Kikkawa et al 1982 JBC 257(22):13341" \
"The process of parameterization is described in detail" \
"in several places. See Supplementary notes to " \
"Bhalla and Iyengar 1999 Science 284:92-96, available at the site" \
"http://www.ncbs.res.in/~bhalla/ltploop/pkc_example.html" \
"The parameterization is also described in a book chapter:" \
"Bhalla, 2000: Simulations of Biochemical Signaling in" \
"Computational Neuroscience: Realistic Modeling for Experimentalists." \
"Ed. E. De Schutter. CRC Press." \
""
call /kinetics/PKC/PKC-Ca/notes LOAD \
"This intermediate is strongly indicated by the synergistic" \
"activation of PKC by combinations of DAG and Ca, as well" \
"as AA and Ca. PKC by definition also has a direct Ca-activation," \
"to which this also contributes."
call /kinetics/PKC/PKC-act-by-Ca/notes LOAD \
"This Kd is a straightforward result from the Schaechter and Benowitz" \
"1993 J Neurosci 13(10):4361 curves. The time-course is based on the" \
"known rapid activation of PKC and also the fact that Ca association" \
"with proteins is typically quite fast. My guess is that this tau of" \
"2 sec is quite conservative and the actualy rate may be much faster." \
"The parameter is quite insensitive for most stimuli." \
"" \
""
call /kinetics/PKC/PKC-act-by-DAG/notes LOAD \
"Ca.PKC interaction with DAG is modeled by this reaction." \
"Kf based on Shinomura et al PNAS 88 5149-5153 1991 and" \
"Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and uses" \
"the constraining procedure referred to in the general" \
"notes for PKC."
call /kinetics/PKC/PKC-Ca-to-memb/notes LOAD \
"Membrane translocation is a standard step in PKC activation." \
"It also turns out to be necessary to replicate the curves" \
"from Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \
"and Shonomura et al 1991 PNAS 88:5149-5153. These rates" \
"are constrained by matching the curves in the above papers and" \
"by fixing a rather fast (sub-second) tau for PKC activation."
call /kinetics/PKC/PKC-DAG-to-memb/notes LOAD \
"membrane translocation step for Ca.DAG.PKC complex." \
"Rates constrained from Shinomura et al 1991 PNAS 88:5149-5153" \
" and Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \
"as derived in the references cited in PKC general notes."
call /kinetics/PKC/PKC-act-by-Ca-AA/notes LOAD \
"Ca-dependent AA activation of PKC." \
"Note that this step combines the AA activation and also the " \
"membrane translocation." \
"From Schaechter and Benowitz 1993 J Neurosci 13(10):4361"
call /kinetics/PKC/PKC-act-by-DAG-AA/notes LOAD \
"Membrane translocation step for PKC-DAG-AA complex." \
"Rates from matching concentration-effect data in our" \
"two main references:" \
"Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and" \
"Shinomura et al 1988 PNAS 88: 5149-5153"
call /kinetics/PKC/PKC-DAG-AA*/notes LOAD \
"Membrane translocated form of PKC-DAG-AA complex."
call /kinetics/PKC/PKC-Ca-AA*/notes LOAD \
"Membrane bound and active complex of PKC, Ca and AA."
call /kinetics/PKC/PKC-Ca-memb*/notes LOAD \
"This is the direct Ca-stimulated activity of PKC."
call /kinetics/PKC/PKC-DAG-memb*/notes LOAD \
"Active, membrane attached form of Ca.DAG.PKC complex."
call /kinetics/PKC/PKC-basal*/notes LOAD \
"This is the basal PKC activity which contributes about" \
"2% to the maximum."
call /kinetics/PKC/PKC-basal-act/notes LOAD \
"Basal activity of PKC is quite high, about 10% of max." \
"See Schaechter and Benowitz 1993 J Neurosci 13(10):4361 and" \
"Shinomura et al 1991 PNAS 88:5149-5153. This is partly due to" \
"basal levels of DAG, AA and Ca, but even when these are taken" \
"into account (see the derivations as per the PKC general notes)" \
"there is a small basal activity still to be accounted for. This" \
"reaction handles it by giving a 2% activity at baseline."
call /kinetics/PKC/PKC-AA*/notes LOAD \
"This is the membrane-bound and active form of the PKC-AA complex." \
""
call /kinetics/PKC/PKC-act-by-AA/notes LOAD \
"AA stimulates PKC activity even at rather low Ca." \
"Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \
"Note that this one reaction combines the initial interaction" \
"and also membrane translocation."
call /kinetics/PKC/PKC-Ca-DAG/notes LOAD \
"This is the active PKC form involving Ca and DAG." \
"It has to translocate to the membrane."
call /kinetics/PKC/PKC-n-DAG/notes LOAD \
"Binding of PKC to DAG, non-Ca dependent." \
"" \
"Kf based on Shinomura et al PNAS 88 5149-5153 1991" \
"Tau estimated as fast and here it is about the same time-course" \
"as the formation of DAG so it will not be rate-limiting."
call /kinetics/PKC/PKC-DAG/notes LOAD \
"This is a DAG-bound intermediate used in synergistic activation" \
"of PKC by DAG and AA."
call /kinetics/PKC/PKC-n-DAG-AA/notes LOAD \
"This is one of the more interesting steps. Mechanistically" \
"it does not seem necessary at first glance. Turns out that" \
"one needs this step to quantitatively match the curves" \
"in Schaechter and Benowitz 1993 J Neurosci 13(10):4361" \
"and Shinomura et al 1991 PNAS 88:5149-5153. There is" \
"a synergy between DAG and AA activation even at low" \
"Ca levels, which is most simply represented by this reaction." \
"Tau is assumed to be fast." \
"Kd comes from matching the experimental curves."
call /kinetics/PKC/PKC-DAG-AA/notes LOAD \
"Complex of PKC, DAG and AA giving rise to synergistic" \
"activation of PKC by DAG and AA at resting Ca." \
""
call /kinetics/PKC/PKC-cytosolic/notes LOAD \
"Marquez et al J. Immun 149,2560(92) est 1e6/cell for chromaffin cells" \
"" \
"Kikkawa et al 1982 JBC 257(22):13341 have PKC levels in brain at " \
"about 1 uM." \
"" \
"The cytosolic form is the inactive PKC. This is really a composite" \
"of three isoforms: alpha, beta and gamma which have slightly" \
"different properties and respond to different combinations of" \
"Ca, AA and DAG."
call /kinetics/DAG/notes LOAD \
"Baseline in model is 11.661 uM." \
"DAG is pretty nasty to estimate. In this model we just hold" \
"it fixed at this baseline level. Data sources are many and" \
"varied and sometimes difficult to reconcile. " \
"Welsh and Cabot 1987 JCB 35:231-245: DAG degradation" \
"Bocckino et al JBC 260(26):14201-14207: " \
"     hepatocytes stim with vasopressin: 190 uM." \
"Bocckino et al 1987 JBC 262(31):15309-15315:" \
"     DAG rises from 70 to 200 ng/mg wet weight, approx 150 to 450 uM." \
"Prescott and Majerus 1983 JBC 258:764-769: Platelets: 6 uM." \
"     Also see Rittenhouse-Simmons 1979 J Clin Invest 63." \
"Sano et al JBC 258(3):2010-2013: Report a nearly 10 fold rise." \
"Habenicht et al 1981 JBC 256(23)12329-12335: " \
"     3T3 cells with PDGF stim: 27 uM" \
"Cornell and Vance 1987 BBA 919:23-36: 10x rise from 10 to 100 uM." \
"" \
"Summary: I see much lower rises in my PLC models," \
"but the baseline could be anywhere from" \
"5 to 100 uM. I have chosen about 11 uM based on the stimulus -response" \
"characteristics from the Schaechter and Benowitz paper and the" \
"Shinomura et al papers." \
"" \
"" \
""
call /kinetics/AA/notes LOAD \
"Arachidonic Acid. This messenger diffuses through membranes" \
"as well as cytosolically, has been suggested as a possible" \
"retrograde messenger at synapses. "
call /kinetics/PKC-active/notes LOAD \
"This is the total active PKC. It is the sum of the respective" \
"activities of " \
"PKC-basal*" \
"PKC-Ca-memb*" \
"PKC-DAG-memb*" \
"PKC-Ca-AA*" \
"PKC-DAG-AA*" \
"PKC-AA*" \
"I treat PKC here in a two-state manner: Either it is in an active" \
"state (any one of the above list) or it is inactive. No matter what " \
"combination of stimuli activate the PKC, I treat it as having the same" \
"activity. The scaling comes in through the relative amounts of PKC" \
"which bind to the respecive stimuli." \
"The justification for this is the mode of action of PKC, which like" \
"most Ser/Thr kinases has a kinase domain normally bound to and blocked" \
"by a regulatory domain. I assume that all the activators simply free" \
"up the kinase domain." \
"A more general model would incorporate a different enzyme activity for" \
"each combination of activating inputs, as well as for each substrate." \
"The current model seems to be a decent and much simpler approximation" \
"for the available data." \
"One caveat of this way of representing PKC is that the summation" \
"procedure assumes that PKC does not saturate with its substrates. " \
"If this assumption fails, then the contributing PKC complexes would" \
"experience changes in availability which would affect their " \
"balance. Given the relatively low percentage of PKC usually activated," \
"and its high throughput as an enzyme, this is a safe assumption under" \
"physiological conditions." \
""
call /kinetics/PKC-active/PKC-act-raf/notes LOAD \
"Rate consts from Chen et al Biochem 32, 1032 (1993)" \
"k3 = 4" \
"Km for this substrate is trickier. Specific substrates are in the" \
"uM range, so we use a higher Km here. This may be too conservative" \
"in which case PKC would have a still higher effect on raf." \
"The presence of this phosphorylation and activation step is from" \
"Kolch et al 1993 Nature 364:249" \
"" \
""
call /kinetics/PKC-active/PKC-inact-GAP/notes LOAD \
"Rate consts are PKC generic rates." \
"This reaction inactivates GAP. The reaction is from the " \
"Boguski and McCormick 1993 review in Nature 366:643-654" \
"The phosphorylation Vmax is 6x higher to account for" \
"balance of GDP-Ras:GDP-Ras."
call /kinetics/PKC-active/PKC-act-GEF/notes LOAD \
"Rate constants are generic PKC rates." \
"See Chen et al 1993 Biochem 32:1032" \
"This reaction activates GEF. Gives >= 2X stim of ras, and" \
"a 2X stim of MAPK over amount from direct phosph of" \
"c-raf. Note that it is a push-pull reaction, and also get" \
"effect through phosph and inact of GAPs." \
""
call /kinetics/PKC-active/PKC-phosph-neurogranin/notes LOAD \
"Rates from Huang et al ABB 305:2 570-580 1993"
call /kinetics/PKC-active/PKC-phosph-ng-CaM/notes LOAD \
"Rates are 60% those of PKC-phosph-neurogranin. See" \
"Huang et al ABB 305:2 570-580 1993"
call /kinetics/PKC-active/phosph-AC2/notes LOAD \
"Phorbol esters have little effect on AC1 or on the Gs-stimulation of" \
"AC2. So in this model we are only dealing with the increase in" \
"basal activation of AC2 induced by PKC" \
"k1 = 1.66e-6" \
"k2 = 16" \
"k3 =4" \
""
call /kinetics/PLA2/notes LOAD \
"Main source of data: Leslie and Channon BBA 1045 (1990) pp 261-270." \
"Fig 6 is Ca curve. Fig 4a is PIP2 curve. Fig 4b is DAG curve. Also see" \
"Wijkander and Sundler JBC 202 (1991) pp873-880;" \
"Diez and Mong JBC 265(24) p14654;" \
"Leslie JBC 266(17) (1991) pp11366-11371" \
"Many inputs activate PLA2. In this model I simply take" \
"each combination of stimuli as binding to PLA2 to give a" \
"unique enzymatic activity. The Km and Vmax of these" \
"active complexes is scaled according to the" \
"relative activation reported in the papers above."
call /kinetics/PLA2/PLA2-cytosolic/notes LOAD \
"cPLA2 IV form has mol wt of 85 Kd." \
"Glaser et al 1993 TIPS 14:92-98." \
"" \
"Calculated cytosolic concentration is ~300 nM from Wijkander and Sundler" \
"1991 Eur J Biochem 202:873" \
"Leslie and Channon 1990 BBA 1045:261 use about 400 nM. " \
"Decent match. Use 400 nM." \
""
call /kinetics/PLA2/PLA2-Ca-act/notes LOAD \
"Direct activation of PLA2 by Ca." \
"From Leslie and Channon BBA 1045 (1990) 261-270 fig6 pp267."
call /kinetics/PLA2/PLA2-Ca*/notes LOAD \
"The generic Ca-activated form ofPLA2." \
"Leslie and Channon 1990 BBA 1045:261."
call /kinetics/PLA2/PLA2-Ca*/kenz/notes LOAD \
"Based on Leslie and Channon 1990 BBA 1045:261, in relation to the" \
"other PLA2 inputs (not including MAPK). Ca alone is rather a " \
"weak input."
call /kinetics/PLA2/PIP2-PLA2-act/notes LOAD \
"Activation of PLA2 by PIP2. From" \
"Leslie and Channon 1990 BBA 1045:261 the stimulation of PLA2" \
"activity by high PIP2 is 7x." \
"In this model we don't really expect any PIP2 stimulus." \
""
call /kinetics/PLA2/PIP2-PLA2*/notes LOAD \
"PLA2 activated by PIP2 alone."
call /kinetics/PLA2/PIP2-PLA2*/kenz/notes LOAD \
"Based on Leslie and Channon 1990 BBA 1045:261."
call /kinetics/PLA2/PIP2-Ca-PLA2-act/notes LOAD \
"Synergistic activation of PLA2 by Ca and PIP2. Again from " \
"Leslie and Channon 1990 BBA 1045:261"
call /kinetics/PLA2/PIP2-Ca-PLA2*/notes LOAD \
"Activated form of PLA2 with PIP2 and Ca bound."
call /kinetics/PLA2/PIP2-Ca-PLA2*/kenz/notes LOAD \
"Based on AA generation by different stimuli according to" \
"Leslie and Channon 1990 BBA 1045:261"
call /kinetics/PLA2/DAG-Ca-PLA2-act/notes LOAD \
"Synergistic activation of PLA2 by Ca and DAG. " \
"Based on Leslie and Channon 1990 BBA 1045:261" \
"The Kd is rather large and may reflect the complications" \
"in measuring DAG. For this model it is not critical " \
"since DAG is held fixed."
call /kinetics/PLA2/DAG-Ca-PLA2*/notes LOAD \
"Active form of PLA2 with DAG and Ca bound. DAG and Ca act in" \
"combination hence the need for this form in the model." \
"Leslie and Channon (199) BBA 1045:261-270"
call /kinetics/PLA2/DAG-Ca-PLA2*/kenz/notes LOAD \
"Based on Leslie and Channon 1990 BBA 1045:261."
call /kinetics/PLA2/APC/notes LOAD \
"arachodonylphosphatidylcholine is the favoured substrate" \
"from Wijkander and Sundler, JBC 202 pp 873-880, 1991." \
"Their assay used 30 uM substrate, which is what the kinetics in" \
"this model are based on. For the later model we should locate" \
"a more realistic value for APC. For now it is treated as" \
"a buffered metabolite."
call /kinetics/PLA2/Degrade-AA/notes LOAD \
"Degradation pathway for AA." \
"APC is a convenient buffered pool to dump it back into, though the" \
"actual metabolism is probably far more complex." \
"For the purposes of the full model we use a rate of degradation of" \
"0.4/sec to give a dynamic range of AA comparable to what is seen" \
"experimentally." \
"Wijkander and Sundler 1991 Eur J Biochem 202:873" \
"Leslie and Channon 1990 BBA 1045:261"
call /kinetics/PLA2/PLA2*-Ca/notes LOAD \
"Phosphorylated and active form of PLA2. Several kinases act on it:" \
"PKA: Wightman et al JBC 257 pp6650 1982" \
"PKC: Many refs, eg Gronich et al JBC 263 pp 16645, 1988 but see Lin etal" \
"MAPK: Lin et al, Cell 72 pp 269, 1993.  Show 3x with MAPK but not PKC alone" \
"The Nemenoff assays are conducted in rather high Ca so I have" \
"assumed a Ca binding step."
call /kinetics/PLA2/PLA2*-Ca/kenz/notes LOAD \
"This form should be 3 to 6 times as fast as the Ca-only form, from" \
"Lin et al 1993 Cell 269-278" \
"Nemenoff et al 1993 JBC 268:1960" \
"Several forms contribute to the Ca-stimulated form, so this rate has" \
"to be a factor larger than their total contribution. " \
"I assign Vmax as the scale factor here because there is lots of APC" \
"substrate, so all the PLA2 complex enzymes are limited primarily by Vmax."
call /kinetics/PLA2/PLA2*/notes LOAD \
"Phosphorylated PLA2. The site differs from the site" \
"phosphorylated by PKC. See" \
"Nemenoff et al 1993 JBC 268(3):1960-1964"
call /kinetics/PLA2/PLA2*-Ca-act/notes LOAD \
"Nemenoff et al 1993 JBC 268:1960 report a 2X to 4x activation of PLA2" \
"by MAPK, which seems dependent on Ca as well. This reaction " \
"represents this activation. Rates are scaled to give appropriate" \
"fold activation."
call /kinetics/PLA2/dephosphorylate-PLA2*/notes LOAD \
"Dephosphorylation reaction to balance MAPK phosphorylation of PLA2." \
"This is probably mediated by PP2A. " \
"Rates determined to keep the balance of phosphorylated and" \
"non-phosphorylated PLA2 reasonable. The constraining factor" \
"is the fold activation of PLA2 by MAPK."
call /kinetics/MAPK*/notes LOAD \
"This molecule is phosphorylated on both the tyr and thr residues and" \
"is active: Seger et al 1992 JBC 267(20):14373" \
"The rate consts are from two sources: Combine Sanghera et al" \
"JBC 265(1) :52-57 with Nemenoff et al JBC 93 pp 1960 to get" \
" k3 = 10, k2 = 40, k1 = 3.25e-6"
call /kinetics/MAPK*/MAPK*/notes LOAD \
"Km = 25uM @ 50 uM ATP and 1mg/ml MBP (huge XS of substrate)" \
"Vmax = 4124 pmol/min/ml at a conc of 125 pmol/ml of enz." \
"Numbers are from Sanghera et al JBC 265 pp 52 , 1990. " \
"From Nemenoff et al 1993 JBC 268(3):1960-1964 - using Sanghera's 1e-4 ratio" \
"of MAPK to protein, we get k3 = 7/sec from 1000 pmol/min/mg total " \
"protein in fig 5" \
"I take the Vmax to be higher for PLA2 given the fold activation of PLA2" \
"by MAPK. This is actually a balance term between MAPK and the dephosphorylation" \
"step." \
""
call /kinetics/MAPK*/MAPK*-feedback/notes LOAD \
"Ueki et al JBC 269(22):15756-15761 show the presence of" \
"this step, but not the rate consts, which are derived from" \
"Sanghera et al  JBC 265(1):52-57, 1990, see the deriv in the" \
"MAPK* notes."
call /kinetics/MAPK*/phosph_Sos/notes LOAD \
"See Porfiri and McCormick JBC 271:10 pp5871 1996 for the" \
"existence of this step. We'll take the rates from the ones" \
"used for the phosph of Raf by MAPK." \
"Sep 17 1997: The transient activation curve matches better" \
"with k1 up  by 10 x."
call /kinetics/temp-PIP2/notes LOAD \
"This is a steady PIP2 input to PLA2. The sensitivity" \
"of PLA2 to PIP2 discussed below" \
"does not match with the reported free levels which are" \
"used by the phosphlipase Cs. My understanding is that" \
"there may be different pools of PIP2 available for stimulating" \
"PLA2 as opposed to being substrates for PLCs. For that reason" \
"I have given this PIP2 pool a separate identity. As it is" \
"a steady input this is not a problem in this model." \
"" \
"Majerus et al Cell 37:701-703 report a brain concentration of" \
"0.1 - 0.2 mole %" \
"Majerus et al Science 234:1519-1526 report a huge range of " \
"concentrations: from 1 to 10% of PI content, which is in turn" \
"2-8% of cell lipid. This gives 2e-4 to 8e-3 of cell lipid." \
"In concentrations in total volume of cell (a somewhat strange" \
"number given the compartmental considerations) this comes to" \
"anywhere from 4 uM to 200 uM." \
"" \
"PLA2 is stim 7x by PIP2 (Leslie and Channon BBA 1045:261(1990) " \
"Leslie and Channon say PIP2 is present at 0.1 - 0.2mol% range in membs," \
"so I'll use a value at the lower end of the scale for basal PIP2."
call /kinetics/Glu/notes LOAD \
"Varying the amount of (steady state) glu between .01 uM and up, the" \
"final amount of G*GTP complex does not change much. This means that" \
"the system should be reasonably robust wr to the amount of glu in the" \
"synaptic cleft. It would be nice to know how fast it is removed." \
"Schoepp et al 1990 TIPS 11:508-515 give a range of Glu EC50 from rat" \
"brain in the range 120 to 1000 uM." \
"Nicoletti 1986 PNAS 83:1931-1935 and" \
"Schoepp and Johnson 1989 J Neurochem 53:1865-1870 " \
"give an off time of at least 30 sec."
call /kinetics/PLCbeta/notes LOAD \
"Phospholipase C beta. This model only incorporates Ca and Gq regulation," \
"though there is evidence to show that many things, from kinase to " \
"phosphatidic acid all regulate its activity. There are various subtypes" \
"of PLCbeta: 1, 2, 3 and probably more. This version is not specific" \
"enough to be subtyped." \
"Primary refs:" \
"Homma et al 1988 JBC 263(14):6592" \
"Ryu et al 1987 JBC 262(26):12511" \
"Sternweis et al 1992 Phil Trans Roy Soc Lond" \
"and especially" \
"Smrcka et al 1991 Science 251:804-807"
call /kinetics/PLCbeta/Act-PLC-Ca/notes LOAD \
"Affinity for Ca = 1uM without AlF, 0.1 with:" \
" from Smrcka et al science 251 pp 804-807 1991" \
"Assigned affinity to a Kd of 0.333 to maintain" \
"detailed balance. "
call /kinetics/PLCbeta/PLC/notes LOAD \
"Total PLC = 0.8 uM see Ryu et al JBC 262 (26) pp 12511 1987"
call /kinetics/PLCbeta/Degrade-IP3/notes LOAD \
"The enzyme is IP3 5-phosphomonesterase. about 45K. Actual products" \
"are Ins(1,4)P2, and cIns(1:2,4,5)P3.  review in Majerus et al Science 234" \
"1519-1526, 1986." \
"Meyer and Stryer 1988 PNAS 85:5051-5055 est decay of IP3 at" \
" 1-3/sec"
call /kinetics/PLCbeta/Inositol/notes LOAD \
"Very simplified degradation product of IP3. There is a very interesting" \
"and complex phosphorylation/dephosphorylation cascade on the inositol" \
"phosphates, but that is outside the scope of this model."
call /kinetics/PLCbeta/Degrade-DAG/notes LOAD \
"" \
"Rates based on basal and activation levels of DAG."
call /kinetics/PLCbeta/PC/notes LOAD \
"Phosphatidylcholine is the main (around 55%) metabolic product of DAG," \
"follwed by PE (around 25%). Ref is Welsh and Cabot, JCB35:231-245(1987)"
call /kinetics/PLCbeta/PLC-Ca/notes LOAD \
"Ca-bound form of PLCbeta. This form is moderately active. Reviewed in" \
"Sternweis et al 1992 Phil Trans Roy Soc. Lond."
call /kinetics/PLCbeta/PLC-Ca/PLC-Ca/notes LOAD \
"From Sternweis et al Phil Trans R Soc Lond 1992, also matched by Homma et al." \
"Km of 20 is higher than for the Gq bound form, but Vmax is about 1/3 of the" \
"Gq form."
call /kinetics/PLCbeta/Act-PLC-by-Gq/notes LOAD \
"Affinity for Gq is > 20 nM (Smrcka et al Science251 804-807 1991)" \
"so [Gq].kf = kb so 40nM * 6e5 = kb/kf = 24e3 so kf = 4.2e-5, kb =1" \
""
call /kinetics/PLCbeta/Inact-PLC-Gq/notes LOAD \
"This process is assumed to be directly caused by the inactivation of" \
"the G*GTP to G*GDP. Hence, " \
"kf = .013 /sec = 0.8/min, same as the rate for Inact-G." \
"kb = 0 since this is irreversible." \
"We may be" \
"interested in studying the role of PLC as a GAP. If so, the kf would be faster here" \
"than in Inact-G"
call /kinetics/PLCbeta/PLC-Ca-Gq/notes LOAD \
"This should really be labelled Ca.GTP.Gq_alpha.PLC" \
"This is the activated form of the enzyme." \
""
call /kinetics/PLCbeta/PLC-Ca-Gq/PLCb-Ca-Gq/notes LOAD \
"From Sternweis et al, Phil Trans R Soc Lond 1992, and the values from" \
"other refs eg Homma et al JBC 263(14) pp6592 1988 match." \
"In this model I have rather low values for PIP2. The Km values" \
"are low to match. Sternweis mentions a 5 uM Km which is what I use" \
"here, but the Homma paper suggests about 20x higher Km, which" \
"would also fit with 20x higher PIP2. So that parameter, though it is" \
"off, cancels out and the overall rate would be the same." \
"Vmax is about 23 umol/min/mg at high Ca from Sternweis or about 60/sec." \
"This model value is a little lower than that."
call /kinetics/PLCbeta/PLC-Gq/notes LOAD \
"Gq-bound form of PLC beta. "
call /kinetics/PLCbeta/PLC-bind-Gq/notes LOAD \
"this binding does not produce active PLC. This step was needed to" \
"implement the described (Smrcka et al) increase in affinity for Ca" \
"by PLC once Gq was bound." \
"The kinetics are the same as the binding step for Ca-PLC to Gq." \
"Kd is constrained by detailed balance." \
""
call /kinetics/PLCbeta/PLC-Gq-bind-Ca/notes LOAD \
"this step has a high affinity of 0.1 uM for Ca, from " \
"Smrcka et al 1991 Science 251:804-807" \
"so kf /kb = 1/6e4 = 1.666e-5:1. See the Act-PLC-by-Gq reaction." \
"" \
"Raised kf to 5e-5 based on match to conc-eff" \
"curves from Smrcka et al."
call /kinetics/BetaGamma/notes LOAD \
"The betagamma subunits of Gq. This is an approximation to the possible" \
"combinations of betagamma subunits. Here they are all treated as a " \
"single pool. "
call /kinetics/G*GTP/notes LOAD \
"Activated G protein. Berstein et al indicate that about 20-40% of the total" \
"Gq alpha should bind GTP at steady stimulus."
call /kinetics/G*GDP/notes LOAD \
"This should correctly be called GDP.G_alpha. The name is preserved for" \
"backward compatibility reasons."
call /kinetics/Gq/notes LOAD \
"The model for the Gq pathway plus its activators, here represented" \
"by the metabotropic glutamate receptor. " \
"We assume GTP is present in fixed amounts, so we leave it out" \
"of the explicit equations in this model. Normally we would expect it" \
"to associate along with the G-Receptor-ligand complex." \
"Most info is from Berstein et al JBC 267:12 8081-8088 1992" \
"Structure of receptor activation of Gq from " \
"Fay et al Biochem 30 5066-5075 1991" \
"This mGluR/Gq model lacks a mechanism for receptor desensitization. "
call /kinetics/Gq/RecLigandBinding/notes LOAD \
"" \
"From Martin et al FEBS Lett 316:2 191-196 1993 we have Kd = 600 nM" \
"Assuming kb = 10/sec, we get kf = 10/(0.6 uM * 6e5) = 2.8e-5 1/sec/#" \
"The off time for Glu seems pretty slow:" \
"Nicoletti et al 1986 PNAS 83:1931-1935 and" \
"Schoepp and Johnson 1989 J Neurochem 53 1865-1870" \
"indicate it is at least 30 sec. Here we are a little faster because" \
"this is only a small part of the off rate, the rest coming from the" \
"Rec-Gq complex."
call /kinetics/Gq/G-GDP/notes LOAD \
"This is the G-alpha-beta-gamma trimer in association with GDP." \
"" \
"From Pang and Sternweis JBC 265:30 18707-12 1990 we get concentration" \
"estimate of  1.6 uM to 0.8 uM. I use 1 uM which is well within this" \
"range." \
""
call /kinetics/Gq/Basal-Act-G/notes LOAD \
"This is the basal exchange of GTP for GDP. So slow as to be" \
"nearly negligible."
call /kinetics/Gq/Trimerize-G/notes LOAD \
"kf == kg3 = 1e-5 /cell/sec. As usual, there is no back-reaction" \
"kb = 0"
call /kinetics/Gq/Inact-G/notes LOAD \
"From Berstein et al JBC 267:12 8081-8088 1992, kcat for GTPase activity" \
"of Gq is only 0.8/min."
call /kinetics/Gq/mGluR/notes LOAD \
"From Mahama and Linderman, Total # of receptors/cell = 1900" \
"However, the density is likely to be very" \
"high at the synapse." \
"Fay et al Biochem 30 5066-5075 1991 have a value of 60K receptors per" \
"cell for neutrophils which comes to 0.1 uM." \
"Here we have a situation where trying to represent the synapse by" \
"a 10 micron cube gives awkward results. I will scale up to 0.3 uM since" \
"synaptic receptor density is likely to be higher, with the caveat that I" \
"should really be using a more geometrically realistic model."
call /kinetics/Gq/Rec-Glu/notes LOAD \
"Glu-Receptor complex."
call /kinetics/Gq/Rec-Gq/notes LOAD \
"Turns out that a large fraction of the the receptor binds to the G-protein" \
"even in the absence of ligand. This pool represents this step." \
"Fraction of Rec-Gq is 44%  of receptor, from " \
"Fay et al 1991 Biochem 30:5066-5075" \
"Since this is not the same receptor, this value is a bit doubtful. Still," \
"we adjust the rate consts in Rec-bind-Gq to match."
call /kinetics/Gq/Rec-Glu-bind-Gq/notes LOAD \
"This is the k1-k2 equivalent for enzyme complex formation in the" \
"binding of Rec-Glu to Gq." \
"See Fay et al Biochem 30 5066-5075 1991." \
"Closer reading of Fay et al suggests that " \
"kb <= 0.0001, so kf = 1e-8 by detailed balance. This" \
"reaction appears to be neglible."
call /kinetics/Gq/Glu-bind-Rec-Gq/notes LOAD \
"From Fay et al" \
"kb3 = kb = 1.06e-3 which is rather slow." \
"k+1 = kf = 2.8e7 /M/sec= 4.67e-5/sec use 5e-5." \
"However, the Kd from Martin et al may be more appropriate, as this" \
"is Glu not the system from Fay." \
"kf = 2.8e-5, kb = 10" \
"Let us compromise. since we have the Fay model, keep kf = k+1 = 2.8e-5." \
"But kb (k-3) is .01 * k-1 from Fay. Scaling by .01, kb = .01 * 10 = 0.1"
call /kinetics/Gq/Rec-Glu-Gq/notes LOAD \
"This is the ternary complex of receptor, ligand and G protein." \
""
call /kinetics/Gq/Activate-Gq/notes LOAD \
"This reaction is the critical one for activation of Gq. It probably" \
"encapsulates multiple steps. In this approximation the receptor-ligand-" \
"Gprotein complex splits up into GTP.Galpha, rec.ligand complex, and " \
"Gbetagamma. There is a hidden step of exchange of GDP for GTP. The" \
"reaction does not take these into account since it is assumed that" \
"both GTP and GDP levels are tightly regulated by metabolic control." \
"" \
"This is the kcat==k3 stage of the Rec-Glu ezymatic activation of Gq." \
"From Berstein et al actiation is at .35 - 0.7/min" \
"From Fay et al Biochem 30 5066-5075 1991 kf = .01/sec" \
"From Nakamura et al J physiol Lond 474:1 35-41 1994 see time courses." \
"Also (Berstein) 15-40% of gprot is in GTP-bound form on stim."
call /kinetics/Gq/Rec-bind-Gq/notes LOAD \
"From Berstein et al 1992 JBC 267(12):8081-8088 we know that 15-40%" \
"of Gq binds, GTP_gamma_S. Also about 20-30% of Gq is bound to GTP." \
"To get to these values the receptor-Gq amount should be similar. These" \
"rates are designed to give that steady state with a fast tau of 1 sec." \
""
call /kinetics/Gq/mGluRAntag/notes LOAD \
"I implement this as acting only on the Rec-Gq complex, based on" \
"a more complete model PLC_Gq48.g" \
"which showed that the binding to the receptor" \
"alone contributed only a small amount."
call /kinetics/Gq/Antag-bind-Rec-Gq/notes LOAD \
"The rate consts give a total binding affinity of under 0.2 nM, good" \
"for a strong antagonist."
call /kinetics/Gq/Blocked-rec-Gq/notes LOAD \
"This represents the blocked state of the receptor when bound" \
"to a competitive antagonist. Note that this is in the Gq bound form." \
"Simulations had shown that with the available rates, the blocking" \
"was minimal if only the unbound receptor could bind the antagonist."
call /kinetics/MAPK/notes LOAD \
"The Mitogen Activated Protein Kinase (MAPK) cascade model " \
"here includes both the MAPK cascade and" \
"its regulation by MKP-1. MKP-1 is induced upon MAPK" \
"activation, whereas MKP-2 is treated as a steady level of" \
"protein. For the purposes of this version of the model," \
"MKP-1 is kept at a fixed starting value." \
"The phosphatase Protein phosphatase 2 A (PP2A) " \
"is also included in this model to balance the activity of" \
"the kinases."
call /kinetics/MAPK/craf-1/notes LOAD \
"Strom et al 1990 Oncogene 5 pp 345-51 report high general expression" \
"in all tissues." \
"Huang and Ferrell 1996 PNAS 93(19):10078 use a value of 3 nM for oocytes." \
"Here we stick with a much higher expression based on the Strom report." \
""
call /kinetics/MAPK/craf-1*/notes LOAD \
"Singly phosphorylated form of c-raf-1. This is the form that gets" \
"best activated by GTP.Ras."
call /kinetics/MAPK/MAPKK/notes LOAD \
"Conc is from Seger et al JBC 267:20 pp14373 (1992)" \
"mwt is 45/46 Kd" \
"We assume that phosphorylation on both ser and thr is needed for" \
"activiation. See Kyriakis et al Nature 358 417 1992" \
"Initial concentration is 0.18" \
""
call /kinetics/MAPK/MAPK/notes LOAD \
"Mol wt is 42 KDa." \
"conc is from Sanghera et al JBC 265 pp 52 (1990)" \
"They estimate MAPK is 1e-4x total protein, and protein is 15% of cell wt," \
"so MAPK is 1.5e-5g/ml = 0.36uM." \
"Lets use this." \
"Note though that Huang and Ferrell 1996 PNAS 93(19):10078" \
"report 1.2 uM in oocytes." \
"Also note that brain concs may be high." \
"Ortiz et al 1995  J. Neurosci 15(2):1285-1297 report " \
"0.3 ng/ug protein in Cingulate Gyrus and 1.2 ng/ug protein" \
"in nucleus accumbens. In hippocampus 270 ng/mg protein for ERK1 and" \
"820 ng/mg protein for ERK 2. " \
"If 15% of cell weight is protein, that means that about 300 * 0.15 ng/ul" \
"is ERK 1.  ie, 45e-9g/1e-6 litre = 45 mg/litre or about 1 uM. " \
"For non-neuronal tissues a lower value may be better."
call /kinetics/MAPK/craf-1**/notes LOAD \
"Negative feedback by MAPK* by hyperphosphorylating craf-1* gives" \
"rise to this pool." \
"Ueki et al JBC 269(22):15756-15761, 1994" \
""
call /kinetics/MAPK/MAPK-tyr/notes LOAD \
"Haystead et al FEBS Lett. 306(1) pp 17-22 show that phosphorylation" \
"is strictly sequential, first tyr185 then thr183."
call /kinetics/MAPK/MAPKK*/notes LOAD \
"MAPKK phosphorylates MAPK on both the tyr and thr residues, first" \
"tyr then thr. Refs: Seger et al JBC267:20 pp 14373 1992" \
"The MAPKK itself is phosphorylated on ser as well as thr residues." \
"Let us assume that the ser goes first, and that the sequential phosphorylation" \
"is needed. See Kyriakis et al Nature 358 417-421 1992"
call /kinetics/MAPK/MAPKK*/MAPKKtyr/notes LOAD \
"The actual MAPKK is 2 forms from Seger et al JBC 267:20 14373(1992)" \
"Vmax = 150nmol/min/mg" \
"From Haystead et al FEBS 306(1):17-22 we get Km=46.6nM for at least one" \
"of the phosphs." \
"Putting these together:" \
"k3=0.15/sec, ratio of 4 to get k2=0.6." \
"k1=0.75/46.6nM=2.7e-5" \
"In terms of Michaelis-Menten rates, " \
"Km = 0.046, Vmax = 0.15, ratio = 4."
call /kinetics/MAPK/MAPKK*/MAPKKthr/notes LOAD \
"Rate consts same as for MAPKKtyr."
call /kinetics/MAPK/MAPKK-ser/notes LOAD \
"Intermediately phophorylated, assumed inactive, form of MAPKK"
call /kinetics/MAPK/Raf-GTP-Ras*/notes LOAD \
"This is the main activated form of craf. It really refers to" \
"the complex of GTP-Ras with phosphorylated Raf. See" \
"Leevers 1994 Nature 369:411-414 and" \
"Hallberg et al 1994 JBC 269(6):3913-3916." \
"The naming is a bit awkward but kept in this model for " \
"consistency with previous models" \
"(Bhalla and Iyengar 1999 Science 283:381-387)" \
""
call /kinetics/MAPK/Raf-GTP-Ras*/Raf-GTP-Ras*.1/notes LOAD \
"This enzyme activity refers to the complex of phosphorylated Raf and activated" \
"Ras." \
"Starting point for kinetics are the same as for the craf-1* activity, ie.," \
"k1=1.1e-6, k2=.42, k3 =0.105" \
"These are based on Force et al PNAS USA 91 1270-1274 1994 who" \
"report a Km of 0.8 uM and Vmax of ~500 fm/min/ug for MAPKK." \
"These parms cannot reach the observed 4X stim of MAPK. So we" \
"increase the affinity, ie, raise k1 5X to 5.5e-6" \
"which is equivalent to a 5x reduction in Km to about 0.16." \
""
call /kinetics/MAPK/Raf-GTP-Ras*/Raf-GTP-Ras*.2/notes LOAD \
"Same kinetics as other c-raf activated forms. See " \
"Force et al PNAS 91 1270-1274 1994." \
""
call /kinetics/MKP-1/notes LOAD \
"MKP-1 dephosphorylates and inactivates MAPK in vivo: Sun et al Cell 75 " \
"487-493 1993. " \
"See Charles et al PNAS 90:5292-5296 1993 and" \
"Charles et al Oncogene 7 187-190 for half-life of" \
"MKP1/3CH is 40 min. 80% deph of MAPK in 20 min" \
"The protein is 40 KDa." \
"The levels are MKP-1 are highly variable, as it is induced" \
"depending on MAPK activity. This selected value is well below its " \
"induced peak, but sufficiently high so that MAPK will not go into a" \
"runaway activation state."
call /kinetics/MKP-1/MKP1-tyr-deph/notes LOAD \
"The original kinetics from Bhalla and Iyengar Science 1999" \
"have now been modified to obey the k2 = 4 * k3 rule," \
"while keeping kcat and Km fixed. The main constraining" \
"data point is the time course of MAPK dephosphorylation, which this" \
"model satisfies." \
"See Charles et al 1993 PNAS 90:5292-5296 and" \
"Charles et al Oncogene 7:187-190" \
"" \
"Effective Km : 67 nM" \
"kcat = 1.43 umol/min/mg"
call /kinetics/MKP-1/MKP1-thr-deph/notes LOAD \
"See MKP1-tyr-deph"
call /kinetics/Ras-act-craf/notes LOAD \
"Assume binding is fast and limited only by available" \
"Ras*. So kf = kb/[craf-1] " \
"If kb is 1/sec, then kf = 1/0.2 uM = 1/(0.2 * 6e5) = 8.3e-6" \
"Later: Raise it by 10 X to about 1e-4, giving a Kf of 60 for Kb of 0.5" \
"and a tau of approx 2 sec." \
"Based on:" \
"Hallberg et al JBC 269:6 3913-3916 1994, 3% of cellular Raf is" \
"complexed with Ras." \
"This step needed to memb-anchor and activate Raf:" \
"Leevers et al Nature 369 411-414." \
"Also see Koide et al 1993 PNAS USA 90(18):8683-8686"
call /kinetics/PPhosphatase2A/notes LOAD \
"Refs: Pato et al Biochem J 293:35-41(93);" \
"CoInit values span a range depending on source." \
"Pato et al 1993 Biochem J 293:35-41 and" \
"Cohen et al 1988 Meth Enz 159:390-408 estimate 80 nM from muscle" \
"" \
"Zolneierowicz et al 1994 Biochem 33:11858-11867 report" \
"levels of 0.4 uM again from muscle, but expression" \
"is also strong in brain." \
"Our estimate of 0.224 is between these two." \
"" \
"There are many substrates for PP2A in this model, so I put" \
"the enzyme rate calculations here:" \
"Takai&Mieskes Biochem J 275:233-239 have mol wt 36 KDa. They" \
"report Vmax of 119 umol/min/mg i.e. 125/sec for k3 for pNPP substrate," \
"Km of 16 mM. This is obviously unreasonable for protein substrates." \
"For chicken gizzard myosin light chan, we have Vmax = 13 umol/min/mg" \
"or about k3 = 14/sec." \
"" \
"Pato et al 1993 Biochem J 293:35-41 report" \
"caldesmon: Km = 2.2 uM, Vmax = 0.24 umol/min/mg. They do not think " \
"caldesmon is a good substrate. " \
"Calponin: Km = 14.3, Vmax = 5." \
"Our values approximate these." \
"" \
""
call /kinetics/PPhosphatase2A/craf-deph/notes LOAD \
"See parent PPhosphatase2A for parms" \
""
call /kinetics/PPhosphatase2A/MAPKK-deph/notes LOAD \
"See: Kyriakis et al Nature 358 pp 417-421 1992" \
"Ahn et al Curr Op Cell Biol 4:992-999 1992 for this pathway." \
"See parent PPhosphatase2A for parms."
call /kinetics/PPhosphatase2A/MAPKK-deph-ser/notes LOAD \
"See parent PPhostphatase2A description for rate details"
call /kinetics/PPhosphatase2A/craf**-deph/notes LOAD \
"Ueki et al JBC 269(22) pp 15756-15761 1994 show hyperphosphorylation of" \
"craf, so this is there to dephosphorylate it. Identity of phosphatase is" \
"assumed to be PP2A."
call /kinetics/Ras/notes LOAD \
" The main refs for Ras are" \
"Boguski and McCormick Nature 366 643-654 '93 Major review" \
"Eccleston et al JBC 268:36 pp 27012-19" \
"Orita et al JBC 268:34 25542-25546"
call /kinetics/Ras/bg-act-GEF/notes LOAD \
"SoS/GEF is present at 50 nM ie 3e4/cell. BetaGamma maxes out at 9e4." \
"Assume we have 1/3 of the GEF active when the BetaGamma is 1.5e4." \
"so 1e4 * kb = 2e4 * 1.5e4 * kf, so kf/kb = 3e-5. The rate of this equil should" \
"be reasonably fast, say 1/sec" \
""
call /kinetics/Ras/GEF-Gprot-bg/notes LOAD \
"Guanine nucleotide exchange factor. This activates raf by exchanging bound" \
"GDP with GTP. I have left the GDP/GTP out of this reaction, it would be" \
"trivial to put them in. See Boguski & McCormick." \
"Possible candidate molecules: RasGRF, smgGDS, Vav (in dispute). " \
"rasGRF: Kcat= 1.2/min    Km = 680 nM" \
"smgGDS: Kcat: 0.37 /min, Km = 220 nM." \
"vav: Turnover up over baseline by 10X, " \
""
call /kinetics/Ras/GEF-Gprot-bg/GEF-bg_act-ras/notes LOAD \
"Kinetics based on the activation of Gq by the receptor complex in the" \
"Gq model (in turn based on the Mahama and Linderman model)" \
"k1 = 2e-5, k2 = 1e-10, k3 = 10 (I do not know why they even bother with k2)." \
"Lets put k1 at 2e-6 to get a reasonable equilibrium" \
"More specific values from, eg.g: Orita et al JBC 268(34) 25542-25546" \
"from rasGRF and smgGDS: k1=3.3e-7; k2 = 0.08, k3 = 0.02" \
""
call /kinetics/Ras/dephosph-GEF/notes LOAD \
"This rate is based on the known ratio of GDP-Ras to GTP-Ras." \
"Basal: Ras.GTP = 7%" \
"Stimulated 15%" \
"Time course is within 10 min, probably much faster as not" \
"all early data points are there." \
"See Gibbs et al JBC 265(33):20437-20422"
call /kinetics/Ras/inact-GEF/notes LOAD \
"This is the amount of inactive GEF available to the system." \
"The value is the same as the estimated amount of SoS, though" \
"I treat it here as a different pool. Probably several molecules" \
"can function as GEFs and this is a simplification." \
"Orita et al JBC 268(34):25542-25546" \
"Gulbins et al 1994 Mol Cell Biol 14(2):906-913" \
""
call /kinetics/Ras/GEF*/notes LOAD \
"Phosphorylated and thereby activated form of GEF. See, e.g." \
"Orita et al JBC 268:34 25542-25546 1993, Gulbins et al." \
"It is not clear whether there is major specificity for tyr or ser/thr."
call /kinetics/Ras/GEF*/GEF*-act-ras/notes LOAD \
"Kinetics from Orita et al JBC 268(34):25542-25546." \
"Note that the Vmax is slow, but it does match" \
"the slow GTP hydrolysis rates." \
""
call /kinetics/Ras/GTP-Ras/notes LOAD \
"Only a very small fraction (7% unstim, 15% stim) of ras is GTP-bound." \
"Gibbs et al JBC 265(33) 20437" \
""
call /kinetics/Ras/GDP-Ras/notes LOAD \
"GDP bound form. See Rosen et al Neuron 12 1207-1221 June 1994." \
"the activation loop is based on Boguski and McCormick Nature 366 643-654 93" \
"Assume Ras is present at about the same level as craf-1, 0.2 uM." \
"Hallberg et al JBC 269:6 3913-3916 1994 estimate upto 5-10% of cellular" \
"Raf is assoc with Ras. Given that only 5-10% of Ras is GTP-bound, we" \
"need similar amounts of Ras as Raf."
call /kinetics/Ras/Ras-intrinsic-GTPase/notes LOAD \
"This is extremely slow (kf = 1e-4), but it is significant as so little GAP actually" \
"gets complexed with it that the total GTP turnover rises only by" \
"2-3 X (see Gibbs et al, JBC 265(33) 20437-20422) and " \
"Eccleston et al JBC 268(36) 27012-27019" \
"There is no back reaction as we assume this to be a regular" \
"irreversible Michaelis-Menten zeroth order hydrolysis." \
""
call /kinetics/Ras/dephosph-GAP/notes LOAD \
"Assume a reasonably good rate for dephosphorylating it, 0.1/sec." \
"This fits well with resting levels of active kinase and the" \
"degree of activation as well as time-course of turnoff of Ras activation," \
"but data is quite indirect."
call /kinetics/Ras/GAP*/notes LOAD \
"Phosphorylated and inactive GAP." \
"See Boguski and McCormick 1993 Nature 366:643-654 for a review."
call /kinetics/Ras/GAP/notes LOAD \
"GTPase-activating proteins. See Boguski and McCormick 1993 Nature 366:643-654" \
"Turn off Ras by helping to hydrolyze bound GTP. " \
"This one is probably NF1, ie.,  Neurofibromin as it is inhibited by AA and lipids," \
"and expressed in neural cells. p120-GAP is also a possible candidate, but" \
"is less regulated. Both may exist at similar levels." \
"See Eccleston et al JBC 268(36) pp27012-19" \
"Level=.002"
call /kinetics/Ras/GAP/GAP-inact-ras/notes LOAD \
"From Eccleston et al JBC 268(36)pp27012-19 get Kd < 2uM, kcat - 10/sec" \
"From Martin et al Cell 63 843-849 1990 get Kd ~ 250 nM, kcat = 20/min" \
"I will go with the Eccleston figures as there are good error bars (10%)." \
"The two sets of values are reasonably close." \
"k1 = 1.666e-3/sec, k2 = 1000/sec, k3 = 10/sec (note k3 is rate-limiting)" \
"This is one of the rare cases where we have direct info on the" \
"k3 being rate-limiting. Hence the ratio I use for the k2:k3 rates is" \
"100 rather than the usual 4."
call /kinetics/Ras/inact-GEF*/notes LOAD \
"Phosphorylation-inactivated form of GEF. See" \
"Hordijk et al JBC 269:5 3534-3538 1994" \
"and " \
"Buregering et al EMBO J 12:11 4211-4220 1993" \
""
call /kinetics/Ras/CaM-bind-GEF/notes LOAD \
"We have no numbers for this. It is probably between" \
"the two extremes represented by the CaMKII phosph states," \
"and I have used guesses based on this." \
"kf=1e-4" \
"kb=1" \
"The reaction is based on Farnsworth et al Nature 376 524-527" \
"1995"
call /kinetics/Ras/CaM-GEF/notes LOAD \
"See Farnsworth et al Nature 376 524-527 1995"
call /kinetics/Ras/CaM-GEF/CaM-GEF-act-ras/notes LOAD \
"Kinetics same as GEF-bg_act-ras" \
""
call /kinetics/PKA-active/notes LOAD \
"The free catalytic subunit."
call /kinetics/PKA-active/PKA-phosph-GEF/notes LOAD \
"This pathway inhibits Ras when cAMP is elevated. See:" \
"Hordijk et al JBC 269:5 3534-3538 1994" \
"Burgering et al EMBO J 12:11 4211-4220 1993" \
"The rates are the same as used in PKA-phosph-I1"
call /kinetics/PKA-active/PKA-phosph-I1/notes LOAD \
"Numbers from Bramson et al CRC crit rev Biochem" \
"15:2 93-124. They have a huge list of peptide substrates" \
"and I have chosen high-ish rates." \
"These consts give too much PKA activity, so lower Vmax 1/3 since" \
"Cohen et al FEBS Lett 76:182-86 1977 say rate =30% PKA act on " \
"phosphokinase beta." \
""
call /kinetics/PKA-active/PKA-phosph-GAP/notes LOAD \
"This activity is not used in this model."
call /kinetics/PKA-active/phosph-PDE/notes LOAD \
"Same rates as PKA-phosph-I1"
call /kinetics/CaM-Ca4/notes LOAD \
"The four-calcium-bound form of CaM. It is the active form for most" \
"reactions."
call /kinetics/Shc*.Sos.Grb2/notes LOAD \
"This three-way complex is one of the main GEFs for activating Ras."
call /kinetics/Shc*.Sos.Grb2/Sos.Ras_GEF/notes LOAD \
"Rates from Orita et al JBC 268(34):25542-25546"
call /kinetics/EGFR/notes LOAD \
"Epidermal Growth Factor Receptor pathway." \
"Outputs include phosphorylation of Shc which then" \
"couples via Sos/Grb2 to Ras; and direct" \
"phosphorylation of PLC-gamma by the " \
"activated EGFR."
call /kinetics/EGFR/EGFR/notes LOAD \
"Berkers et al JBC 266 say 22K hi aff recs." \
"Sherrill and Kyte Biochemistry 35 use range 4-200 nM." \
"These match pretty well. Using 167 nM."
call /kinetics/EGFR/act_EGFR/notes LOAD \
"Affinity of EGFR for EGF is complex: depends on [EGFR]." \
"We'll assume fixed [EGFR] and use exptal" \
"affinity ~20 nM (see Sherrill and Kyte" \
"Biochem 1996 35 5705-5718, Berkers et al JBC 266:2 922-927" \
"1991, Sorokin et al JBC 269:13 9752-9759 1994). " \
"Tau =~2 min (Davis et al JBC 263:11 5373-5379 1988)" \
"or Berkers Kass = 6.2e5/M/sec, Kdiss=3.5e-4/sec." \
"Sherrill and Kyte have Hill Coeff=1.7" \
""
call /kinetics/EGFR/L.EGFR/notes LOAD \
"This is terribly simplified: there are many interesting" \
"intermediate stages, including dimerization and assoc" \
"with adapter molecules like Shc, that contribute to the" \
"activation of the EGFR."
call /kinetics/EGFR/L.EGFR/phosph_PLC_g/notes LOAD \
"Hsu et al JBC 266:1 603-608 1991" \
"Km = 385 +- 100 uM, Vm = 5.1 +-1 pmol/min/ug for PLC-771." \
"Other sites have similar range, but are not stim as much" \
"by EGF. These rates are improbably slow and are for the " \
"intracellular domain of EGFR alone." \
"Wahl et al JBC 267(15) 10447-10456 1992 reports a tau of 5min for" \
"activation of PLC-gamma in vivo." \
"Also Sherrill and Kyte say turnover # for angiotensin II is" \
"5/min for cell extt, and 2/min for placental. Also see" \
"Okada et al JBC 270(35) 20737-20741 1995" \
" for Shc rates where Km = 0.7 and Vmax = 4.4 pmol/min" \
"To achieve these turnovers and time-courses, we may need to" \
"consider the membrane-plane action of the the receptor, but" \
"for now the rates are consistent with the Wahl et al reports."
call /kinetics/EGFR/L.EGFR/phosph_Shc/notes LOAD \
"Rates from Okada et al JBC 270:35 pp 20737 1995" \
"Km = 0.70 to 0.85 uM, Vmax = 4.4 to 5.0 pmol/min. Unfortunately" \
"the amount of enzyme is not known, the prep is only" \
"partially purified." \
"Time course of phosph is max within 30 sec, falls back within" \
"20 min. Ref: Sasaoka et al JBC 269:51 32621 1994." \
"Use k3 = 0.1 based on this tau." \
""
call /kinetics/EGFR/EGF/notes LOAD \
"Epidermal growth factor."
call /kinetics/EGFR/SHC/notes LOAD \
"There are 2 isoforms: 52 KDa and 46 KDa (See Okada et al" \
"JBC 270:35 pp 20737 1995). They are acted up on by the EGFR" \
"in very similar ways, and apparently both bind Grb2 similarly," \
"so we'll bundle them together here." \
"Sasaoka et al JBC 269:51 pp 32621 1994 show immunoprecs where" \
"it looks like there is at least as much Shc as Grb2. So" \
"we'll tentatively say there is 0.5 uM of Shc."
call /kinetics/EGFR/SHC*/notes LOAD \
"Phosphorylated form of SHC. Binds to the " \
"Sos.Grb2 complex to give the activated GEF form" \
"upstream of Ras."
call /kinetics/EGFR/dephosph_Shc/notes LOAD \
"Time course of decline of phosph is 20 min from" \
"Sasaoka et al 1994 JCB 269(51):32621. Part of this is" \
"the turnoff time of the EGFR itself. Lets assume a tau of" \
"10 min for this dephosph, which means a Kf of 0.0016667"
call /kinetics/EGFR/Internal_L.EGFR/notes LOAD \
"The internalized and inactive ligand-bound EGFR. There is lots" \
"of interesting cell biology which we are ignoring here."
call /kinetics/EGFR/Internalize/notes LOAD \
"See Helin and Beguinot JBC 266:13 1991 pg 8363-8368." \
"In Fig 3 they have internalization tau about 10 min, " \
"equil at about 20% EGF available. So kf = 4x kb, and" \
"1/(kf + kb) = 600 sec so kb = 1/3K = 3.3e-4," \
"and kf = 1.33e-3. This doesn't take into account the" \
"unbound receptor, so we need to push the kf up a bit, to" \
"0.002" \
"This reaction is treated as reversible, thereby" \
"making the approximation that the re-insertion of EGFR into the" \
"membrane is handled by the same process going " \
"backwards. "
call /kinetics/Sos/notes LOAD \
"This represents the mSos protein and the Grb2 adapter protein" \
"involved in Ras activation. This module provides for input from" \
"RTKs as well as feedback inhibition from MAPK, although the" \
"latter is not implemented in this specific model."
call /kinetics/Sos/Shc_bind_Sos.Grb2/notes LOAD \
"Sasaoka et al JBC 269:51 pp 32621 1994, table on pg" \
"32623 indicates that this pathway accounts for about " \
"50% of the GEF activation. (88% - 39%). Error is large," \
"about 20%. Fig 1 is most useful in constraining rates." \
"" \
"Chook et al JBC 271:48 pp 30472, 1996 say that the Kd is" \
"0.2 uM for Shc binding to EGFR. The Kd for Grb direct binding" \
"is 0.7, so we'll ignore it."
call /kinetics/Sos/Sos*.Grb2/notes LOAD \
"Inactive complex of Sos* with Grb2 due to phosphorylation of the Sos." \
"See Porfiri and McCormick 1996 JBC 271(10):5871."
call /kinetics/Sos/Grb2_bind_Sos*/notes LOAD \
"Same rates as Grb2_bind_Sos: Porfiri and McCormick JBC" \
"271:10 pp 5871 1996 show that the binding is not affected" \
"by the phosphorylation."
call /kinetics/Sos/Grb2/notes LOAD \
"There is probably a lot of it in the cell: it is also known" \
"as Ash (abundant src homology protein). Also " \
"Waters et al JBC 271:30 18224 1996 say that only a small" \
"fraction of cellular Grb is precipitated out when SoS is" \
"precipitated. As most of the Sos seems to be associated" \
"with Grb2, it would seem like there is a lot of the latter." \
"Say 1 uM. This would comfortably saturate the SoS."
call /kinetics/Sos/Sos.Grb2/notes LOAD \
"For simplicity I treat the activation of Sos as involving a" \
"single complex comprising Sos, Grb2 and Shc*. This is" \
"reasonably documented:" \
"Sasaoka et al 1994 JBC 269(51):32621-5" \
"Chook et al JBC 1996 271(48):30472" \
""
call /kinetics/Sos/Sos*/notes LOAD \
"Phosphorylated form of  SoS. Nominally this is an inactivation step" \
"mediated by MAPK, see Profiri and McCormick 1996 JBC 271(10):5871." \
"I have not put this inactivation in this pathway so this molecule " \
"currently only represents a potential interaction point."
call /kinetics/Sos/dephosph_Sos/notes LOAD \
"The best clue I have to these rates is from the time" \
"courses of the EGF activation, which is around 1 to 5 min." \
"The dephosph would be expected to be of the same order," \
"perhaps a bit longer. Lets use 0.002 which is about 8 min." \
"Sep 17: The transient activation curve matches better with" \
"kf = 0.001"
call /kinetics/Sos/Grb2_bind_Sos/notes LOAD \
"As there are 2 SH3 domains, this reaction could be 2nd order." \
"I have a Kd of 22 uM from peptide binding (Lemmon et al " \
"JBC 269:50 pg 31653). However, Chook et al JBC 271:48 pg30472" \
"say it is 0.4uM with purified proteins, so we believe them." \
"They say it is 1:1 binding." \
"Porfiri and McCormick JBC 271 also have related data." \
"After comparing with the time-course of 1 min and the efficacy" \
"of activation of Ras, settle on Kd of 0.672 which is close" \
"to the Chook et al value."
call /kinetics/Sos/Sos/notes LOAD \
"I have tried using low (0.02 uM) initial concs, but these" \
"give a very flat response to EGF stim although the overall" \
"activation of Ras is not too bad. I am reverting to 0.1 " \
"because we expect a sharp initial response, followed by" \
"a decline." \
""
call /kinetics/PLC_g/notes LOAD \
"This group represents phospholipase C -gamma. Originally PLC-II." \
"Ryu et al JBC 262(26) 12511-12518 1987. " \
"Homma et al Biochem J 269:13-18 is also a good source of early info." \
""
call /kinetics/PLC_g/PLC_g/notes LOAD \
"Amount from Homma et al JBC 263:14 6592-6598 1988." \
"Source is rat brain. "
call /kinetics/PLC_g/Ca_act_PLC_g/notes LOAD \
"Nice curves from Homma et al JBC 263:14 6592-6598 1988 " \
"Fig 5c. The activity falls above 10 uM, but that is too high" \
"to reach physiologically anyway, so we'll ignore the higher" \
"pts and match the lower ones only. Half-max at 1 uM." \
"But  Wahl et al JBC 267:15 10447-10456 1992 have half-max" \
"at 56 nM which is what I'll use."
call /kinetics/PLC_g/Ca_act_PLC_g*/notes LOAD \
"Again, we refer to Homma et al and Wahl et al, for preference" \
"using Wahl et al JBC 267(15):10447-10456 1992. " \
"Half-Max of the phosph form is at 316 nM." \
"Use kb of 10 as this is likely to be pretty fast." \
"As we are phosphorylating the Ca-bound form," \
"equils have shifted. kf should now be 2e-5 (Kf = 12)" \
"to match the reported half-max." \
""
call /kinetics/PLC_g/dephosph_PLC_g/notes LOAD \
"This is a generic balancing dephosphorylation step for the" \
"PLC. Rates are determined by considering balance between " \
"phosph and" \
"non-phosph forms of PLC-gamma. Wahl et al " \
"JBC 267(15) 10447-10456 1992 put the ratio at" \
"50% phosph form in cytoplasm, about 20% in membrane." \
""
call /kinetics/PLC_g/PLC_G*/notes LOAD \
"The phosphorylated form without calcium is not very active." \
"I assume zero activity at zero calcium. As the halfmax for Ca" \
"binding is around 100 nM" \
"from Wahl et al JBC 267(15) 10447-10456 1992," \
"it seems that basal calcium will account for respectable basal" \
"activity."
call /kinetics/PLC_g/Ca.PLC_g/PIP2_hydrolysis/notes LOAD \
"Wahl et al JBC 267(15) 10447-10456 1992." \
" Homma et al JBC 263:14 1988 pp 6592. These" \
"parms are the Ca-stimulated form." \
"This is close to Wahl's" \
"figure 7, which I am using as reference." \
"Also see Nakanishi et al Biochem J 256 453-459 1998," \
"Nishibe et al Science 250 :1253-1256" \
"This model uses a rather low PIP2 of 10 uM."
call /kinetics/PLC_g/Ca.PLC_g*/PIP2_hydrolysis/notes LOAD \
"Mainly Homma et al JBC 263:14 1988 pp 6592. These" \
"parms are the Ca-stimulated form. " \
" Wahl et al JBC 267:15 10447-10456 1992 say" \
"that the tyrosine phosphorylated form" \
"has 7X higher affinity for substrate than control." \
"" \
"The PIP2 levels in this model are rather low, at 10 uM."
call /kinetics/CaMKII/notes LOAD \
"Main reference here is the review by Hanson and Schulman, Ann Rev Biochem" \
"1992 vol 61 pp 559-601. Most of the mechanistic details and a few constants" \
"are derived from there. Many kinetics are from Hanson and Schulman JBC" \
"267:24 17216-17224 1992." \
"The enzymes look a bit complicated." \
"Actually it is just 3 reactions for different sites," \
"by 4 states of CaMKII, defined by the phosphorylation state." \
"This model approximates the fact that the enzyme is actually present as" \
"a decamer/dodecamer. It does so by treating the autophosphorylation reactions" \
"as being independent of the concentration of CaMKII. Also the rates for" \
"the autophosphorylation steps have been scaled to fit this " \
"approximation. "
call /kinetics/CaMKII/CaMKII/notes LOAD \
"Huge concentration of CaMKII. In PSD it is 20-40% of protein," \
" so we assume it is around" \
"2.5% of protein in spine as a whole. This level is so high it is unlikely to" \
" matter much if we are off a bit. This comes to about 70 uM." \
"Seen the review:" \
"Hanson and Schulman 1992 Ann. Rev. Biuochem 60:559-601"
call /kinetics/CaMKII/CaMKII-CaM/notes LOAD \
"This is the regular, CaM-activated form of CaMKII." \
"See the review" \
"Hanson and Schulman 1992 Ann. Rev. Biochem 60:559-601"
call /kinetics/CaMKII/CaMKII-thr286*-CaM/notes LOAD \
"From Hanson and Schulman, the thr286 is responsible for autonomous activation" \
"of CaMKII."
call /kinetics/CaMKII/CaMKII***/notes LOAD \
"From Hanson and Schulman, the CaMKII does a lot of autophosphorylation" \
"just after the CaM is released. This prevents further CaM binding and renders" \
"the enzyme quite independent of Ca."
call /kinetics/CaMKII/CaMKII-bind-CaM/notes LOAD \
"This is tricky. There is some cooperativity here arising from interactions" \
"between the subunits of the CAMKII holoenzyme. However, the" \
"stoichiometry is 1. " \
"Kd = 0.1 uM. Rate is fast (see Hanson et al Neuron 12 943-956 1994)" \
"Hanson and Schulman 1992 AnnRev Biochem 61:559-601" \
"give tau for dissoc as 0.2 sec at low Ca, 0.4 at high." \
"Low Ca = 100 nM = physiol."
call /kinetics/CaMKII/CaMK-thr286-bind-CaM/notes LOAD \
"Affinity is up 1000X over the unphosphorylated CaMKII, which makes the" \
"Kd of 0.1 nM. See Hanson et al 1994 Neuron 12:943-956." \
"Time to release is about 20 sec, so the kb is OK at 0.1/sec." \
"as tested by a few runs." \
""
call /kinetics/CaMKII/CaMKII-thr286/notes LOAD \
"The threonine-286 phosphorylated form of CaMKII. It is likely" \
"to be a short-lived intermediate, since it will be phosphorylated further" \
"as soon as the CAM falls off."
call /kinetics/CaMKII/CaMK-thr306/notes LOAD \
"This forms due to basal autophosphorylation, but I think it has to be" \
"considered as a pathway even if some CaM is floating around. In either" \
"case it will tend to block further binding of CaM, and will not display any" \
"enzyme activity. See Hanson and Schulman JBC 267:24 pp17216-17224 1992"
call /kinetics/CaMKII/total-CaMKII/notes LOAD \
"This pool is purely here to provide a single, fixed number," \
"which is the total amount of CaMKII. This is used by the" \
"autophosphorylation steps to scale down the rates so that the" \
"autophosphorylation reactions are independent of CaMKII levels."
call /kinetics/CaMKII/basal-activity/notes LOAD \
"This reaction represents one of the unknowns in CaMK-II" \
"biochemistry: what maintains the basal level of phosphorylation" \
"on thr 286 ? See Hanson and Schulman Ann Rev Biochem 1992" \
"61:559-601, specially pg 580, for review. I have not been able to" \
"find any compelling mechanism in the literature, but fortunately" \
"the level of basal activity is well documented. " \
"Lisman et al propose that the levels of PP1 are very low in the " \
"postsynaptic density, and PP2A is excluded from the PSD, and this would" \
"lead to autophosphorylation at a sustained level."
call /kinetics/CaMKII/tot_CaM_CaMKII/notes LOAD \
"This pool sums the levels of the CaM-bound forms of CaMKII:" \
"CaMKII-CaM + CaMKII-thr286*-CaM. Although their phosphorylation states" \
"are different, the level of activity is about the same so it makes sense" \
"to sum the levels." \
"Hanson et al 1994 Neuron 12:943-956"
call /kinetics/CaMKII/tot_CaM_CaMKII/CaM_act_305/notes LOAD \
"Rates from autocamtide phosphorylation, from " \
"Hanson and Schulman JBC 267:24 17216-17224 1992. See especially Fig 5."
call /kinetics/CaMKII/tot_CaM_CaMKII/CaM_act_286/notes LOAD \
"See Hanson and Schulman 1992 JBC 267(24):17216-17224"
call /kinetics/CaMKII/tot_autonomous_CaMKII/notes LOAD \
"This is the sum total of the various CaM-independent forms of the " \
"kinase. There are actually several possible states here, but I only" \
"consider the forms thr-286 phosphorylated form and the doubly/triply" \
"phosphorylated form including the thr305/306, represented here" \
"as CaMKII***" \
""
call /kinetics/CaMKII/tot_autonomous_CaMKII/auton_305/notes LOAD \
"See Hanson and Schulman 1992 JBC 267(24):17216-17224" \
"for afterburst rates of phosphorylation"
call /kinetics/CaMKII/tot_autonomous_CaMKII/auton_286/notes LOAD \
"The autonomous rate has a slightly higher Km than the CaM-bound rate," \
"but Vmax is the same." \
"Hanson and Schulman 1992 Ann Rev Biochem 61:559-601" \
"and " \
"Hanson and Schulman 1992 JBC 267(24):17216-17224"
call /kinetics/PP1-active/notes LOAD \
"Cohen et al Meth Enz 159 390-408 is main source of info" \
"concentration of enzyme = 1.8 uM"
call /kinetics/PP1-active/Deph-thr286/notes LOAD \
"The rates are from Stralfors et al Eur J Biochem 149 295-303 giving" \
"Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14." \
"Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so" \
"k1 becomes 5.72e-6" \
"Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates" \
"are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10" \
"to 5.72e-7, 1.4, 0.35. " \
"This gives the final Km of 5.1, and Vmax of 0.35/sec."
call /kinetics/PP1-active/Deph-thr305/notes LOAD \
"Dephosphorylation kinetics are assumed to be the same for all" \
"phosphorylation sites on CaMKII. " \
"The rates are from Stralfors et al Eur J Biochem 149 295-303 giving" \
"Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14." \
"Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so" \
"k1 becomes 5.72e-6" \
"Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates" \
"are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10" \
"to 5.72e-7, 1.4, 0.35. " \
"This gives the final Km of 5.1, and Vmax of 0.35/sec."
call /kinetics/PP1-active/Deph-thr306/notes LOAD \
"Dephosphorylation kinetics are assumed to be the same for all" \
"phosphorylation sites on CaMKII. " \
"The rates are from Stralfors et al Eur J Biochem 149 295-303 giving" \
"Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14." \
"Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so" \
"k1 becomes 5.72e-6" \
"Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates" \
"are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10" \
"to 5.72e-7, 1.4, 0.35. " \
"This gives the final Km of 5.1, and Vmax of 0.35/sec."
call /kinetics/PP1-active/Deph-thr286c/notes LOAD \
"Dephosphorylation kinetics are assumed to be the same for all" \
"phosphorylation sites on CaMKII. " \
"The rates are from Stralfors et al Eur J Biochem 149 295-303 giving" \
"Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14." \
"Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so" \
"k1 becomes 5.72e-6" \
"Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates" \
"are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10" \
"to 5.72e-7, 1.4, 0.35. " \
"This gives the final Km of 5.1, and Vmax of 0.35/sec."
call /kinetics/PP1-active/Deph_thr286b/notes LOAD \
"Rates are assumed to be the same for all phosphorylation sites" \
"on CaMKII. " \
"The rates are from Stralfors et al Eur J Biochem 149 295-303 giving" \
"Vmax = 5.7 umol/min giving k3 = 3.5/sec and k2 = 14." \
"Foulkes et al Eur J Biochem 132 309-313 1983 give Km = 5.1 uM so" \
"k1 becomes 5.72e-6" \
"Simonelli 1984 (Grad Thesis, CUNY) showed that other substrates" \
"are about 1/10 rate of phosphorylase a, so we reduce k1,k2,k3 by 10" \
"to 5.72e-7, 1.4, 0.35. " \
"This gives the final Km of 5.1, and Vmax of 0.35/sec."
call /kinetics/PP1-active/Deph-thr305b/notes LOAD \
"This enzyme activity is not actually used in this model." \
""
call /kinetics/CaM/notes LOAD \
"This is the basic Ca-binding-to-CaM model with the addition of " \
"neurogranin as a CaM sequestering molecule." \
"Main data sources are " \
"Forsen et al 1986 Calcium and Cell funciton VI 113_157" \
"Drabikowski and Brzeska 1982 JBC 257(19):11584-11590" \
"Martin et al 1985 Eur J Biochem 151(3):543-550" \
"Stemmer and Klee 1994 Biochem 33:6859-6866" \
"Data is pretty thorough. The Neurogranin info is from several sources esp" \
"Huang et al 1993 ABB 305(2):570-580" \
"Gerendasy et al 1994 JBC 269(35) 22420-22426 is not very quantitative"
call /kinetics/CaM/CaM/notes LOAD \
"There is a LOT of this in the cell: upto 1% of total protein mass. " \
"(Alberts et al, Mol Biol. of the Cell, Garland Publishers)" \
"Say 25 uM. Meyer et al Science 256 1199-1202 1992 refer to studies saying" \
"it is comparable to CaMK levels. " \
""
call /kinetics/CaM/CaM-TR2-bind-Ca/notes LOAD \
"We use the Martin et al 1985 Eur J Biochem 151(3):543-550 rates here, " \
"plus the Drabikowski and Brzeska 1982 JBC 257(19):11584-11590 binding consts." \
"All are scaled by 3X to cell temperature." \
"kf = 2e-10 kb = 72" \
"Stemmer & Klee 1994 Biochem 33:6859-6866 have values of : K1=.9, K2=1.1." \
"Assume 1.0uM for both" \
""
call /kinetics/CaM/CaM-TR2-Ca2-bind-Ca/notes LOAD \
"Stemmer and Klee 1994 Biochem 33:6859-6866" \
"K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get" \
"kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10" \
""
call /kinetics/CaM/CaM-Ca3-bind-Ca/notes LOAD \
"Use K3 = 21.5 uM here from Stemmer and Klee table 3." \
"Stemmer and Klee 1994 Biochem 33:6859-6866" \
"kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10"
call /kinetics/CaM/neurogranin-CaM/notes LOAD \
"This is the CaM-bound form of neurogranin. This CaM is taken out" \
"of circulation and thus reduces the signaling through CaM."
call /kinetics/CaM/neurogranin-bind-CaM/notes LOAD \
"Surprisingly, no direct info on rates from neurogranin at this time." \
"These rates are based on GAP-43 binding studies. As GAP-43 and " \
"neurogranin share near identity in the CaM/PKC binding regions, and also" \
"similarity in phosph and dephosph rates, I am borrowing GAP-43 " \
"kinetic info." \
"See Alexander et al JBC 262:13 6108-6113 1987"
call /kinetics/CaM/neurogranin*/notes LOAD \
"The phosphorylated form of neurogranin" \
" does not bind CaM (Huang et al ABB 305:2 570-580 1993)"
call /kinetics/CaM/neurogranin/notes LOAD \
"Also known as RC3 and p17 and BICKS." \
"Concentration in brain  >> 2 uM from Martzen and Slemmon J Neurosci 64 92-100 1995. " \
"Concentration in dend spines is much higher than " \
"overall, so it could be anywhere from 2 uM to 50. We will estimate" \
"10 uM as a starting point." \
"Gerendasy et al JBC 269:35 22420-22426 1994 have a skeleton model (no" \
"numbers) indicating CaM-Ca(n) binding."
call /kinetics/CaM/dephosph-neurogranin/notes LOAD \
"This is put in to keep the basal levels of neurogranin* experimentally" \
"reasonable. From various papers, specially Ramakers et al JBC 270:23 1995" \
"13892-13898," \
" it looks like the basal level of phosph is between 20 and 40%. I estimate" \
"around 25 % The kf of 0.005 gives around this level at basal PKC" \
"activity levels of 0.1 uM active PKC."
call /kinetics/CaM-Ca3/notes LOAD \
"The TR1 end now begins to bind Ca. This form has 2 Ca's on the" \
"TR2 end, and one on the TR1."
call /kinetics/CaM-TR2-Ca2/notes LOAD \
"This is the intermediate where the TR2 end (the high-affinity end) has" \
"bound the Ca but the TR1 end has not."
call /kinetics/CaM(Ca)n-CaNAB/notes LOAD \
"This pool sums the levels of the CaM.Ca2.CaNAB, CaM.Ca3.CaNAB" \
"and CaM.Ca4.CaNAB pools."
call /kinetics/CaM(Ca)n-CaNAB/dephosph_neurogranin/notes LOAD \
"From Seki et al ABB 316(2):673-679"
call /kinetics/CaM(Ca)n-CaNAB/dephosph_inhib1/notes LOAD \
"Assume the rates are the same when dephosphorylating I1 either" \
"when it is floating freely, or when it is bound to PP1 catalytic" \
"subunit." \
"This is from Liu and Storm 1989 264(22):12800-12804"
call /kinetics/CaM(Ca)n-CaNAB/dephosph-PP1-I*/notes LOAD \
"Liu and Storm JBC 1989 264(22):12800-12804" \
"say Km ~ 5 uM, Vmax = 256 nmol/min/mg ~ 0.34/sec"
call /kinetics/PP1/notes LOAD \
"Protein phosphatase 1. This is the primary dephosphorylating enzyme" \
"for CaMKII in this model. " \
"See Cohen and Cohen JBC 265(36):21435-21438" \
"Cohen 1989 Ann Rev Biochem 58:453-508"
call /kinetics/PP1/I1/notes LOAD \
"I1 is a 'mixed' inhibitor, but at high enz concs it looks like a non-compet" \
"inhibitor (Foulkes et al Eur J Biochem 132 309-313 9183)." \
"We treat it as non-competitive, so it just turns the enzyme off" \
"without interacting with the binding site." \
"Cohen et al 1989 Ann rev Biochem 58:453-508 refer to results where" \
" concentration of the inhibitor is " \
"1.5 to 1.8 uM. In order to get complete inhib of PP1, which is at 1.8 uM," \
"we need >= 1.8 uM." \
"" \
""
call /kinetics/PP1/I1*/notes LOAD \
"Phosphorylated form of the inhibitor. This has a high affinity for" \
"the PP1 catalytic subunit. Upon binding the PP1 is inactivated." \
"Cohen 1989 Ann Rev Biochem 58:453-508"
call /kinetics/PP1/Inact-PP1/notes LOAD \
"K inhib = 1nM from Cohen Ann Rev Bioch 1989, " \
"4 nM from Foukes et al " \
"Assume 2 nM. kf /kb = 8.333e-4" \
"The Kd used here is 0.2 nM. This is small, but unlikely to matter much" \
"as the affinity is so strong that the reaction will be all the way forward" \
"in either case." \
"" \
"Tau < 1 min for inhibition. " \
"Stralfors 1985 Eur J Biochem 149:295-303 fig 8 pg 201."
call /kinetics/PP1/PP1-I1*/notes LOAD \
"This form has the inibitory fragment phosphorylated. The binding" \
"of PP1 is tight when the inhibitory fragment is phosphorylated" \
"Cohen 1989 Ann Rev Biochem 58:453-508"
call /kinetics/PP1/PP1-I1/notes LOAD \
"This form is bound to the non-phosphorylated inibitory subunit" \
"and is prone to dissociate." \
"Cohen 1989 Ann Rev biochem 58:453-508"
call /kinetics/PP1/dissoc-PP1-I1/notes LOAD \
"Assumption is that the affinity of the unphosphorylated form of I1 for" \
"PP1 is extremely weak and that the reaction is essentially all the way" \
"forward. The tau is fast at 1 sec."
call /kinetics/PP2A/notes LOAD \
"Protein phosphatase 2A dephosphorylates the inibitory subunit." \
"This is treated as a basal level of dephosphorylation. More specific" \
"and regulated dephosphorylation occurs through CaN, calcineurin." \
"Cohen 1989: Ann rev Biochem 58:453-508"
call /kinetics/PP2A/PP2A-dephosph-I1/notes LOAD \
"PP2A does most of the dephosph of I1 at basal Ca levels. See" \
"the review by Cohen in Ann Rev Biochem 1989  58:453-508" \
"I use a Km twice that for the preferred substrates of PP2A." \
""
call /kinetics/PP2A/PP2A-dephosph-PP1-I*/notes LOAD \
"PP2A does most of the dephosph of I1 at basal Ca levels. See" \
"the review by Cohen in Ann Rev Biochem 1989  58:453-508" \
"I use a Km twice that for the preferred substrates of PP2A." \
"Here I assume that the dephosph of the PP1-bound form of I1*" \
"will proceed at the same rate as the unbound I1*."
call /kinetics/CaNAB-Ca4/notes LOAD \
"Four calciums bound to CaN. This has an activity " \
"in absence of CaM." \
"Perrino et al 1992 JBC 267(22):15965-15969"
call /kinetics/CaNAB-Ca4/dephosph_inhib1_noCaM/notes LOAD \
"The rates here are so slow I do not know if we should even bother" \
"with this enzyme reaction. These numbers are from Liu and Storm" \
"JBC 1989 264(22):12800-12804" \
"They say that the CaM-free form of CaN operates at about the" \
"same Km of 5 uM, but at a much lower Vmax of 1 nmol/min/mg." \
"Other estimates of activity without CaM suggest 10% activity, which" \
"is what I use here." \
""
call /kinetics/PP2B/notes LOAD \
"Also called Calcineurin." \
"Major sources of info:" \
"Cohen, P Ann Rev Biochem 1989 58:453-508" \
"Mumby and Walker Physiol Rev 73:4 673-699" \
"Stemmer and Klee Biochem 33 1994 6859-6866" \
"Liu and Storm JBC 264:22 1989 12800-12804" \
"This model is unusual: There is actually more expt info than I want to" \
"put in the model at this time." \
"Phosph: Hashimoto and Soderling JBC 1989 264:28 16624-16629 (Not used)"
call /kinetics/PP2B/CaNAB/notes LOAD \
"Calcineurin A and B subunits." \
"We assume that the A and B subunits of PP2B are always bound under" \
"physiological conditions." \
"" \
"Tallant and Cheung '83 Biochem 22 3630-3635 have conc in many " \
"species, average for mammalian brain is around 1 uM."
call /kinetics/PP2B/CaNAB-Ca2/notes LOAD \
"Form of CaN with two Calciums bound."
call /kinetics/PP2B/Ca-bind-CaNAB-Ca2/notes LOAD \
"This process is probably much more complicated and involves CaM." \
"However, as I can't find detailed info I am bundling this into a" \
"single step." \
"Based on Steemer and Klee 1994 Biochem 33:6859-6866, this" \
"specific parm on pg 6863, the Kact is 0.5 uM." \
"Assume binding is fast, 1 sec."
call /kinetics/PP2B/Ca-bind-CaNAB/notes LOAD \
"going on the experience with CaM, we put the fast (high affinity)" \
"sites first. We only know (Stemmer and Klee) that the affinity is < 70 nM." \
"Assuming 10 nM at first. This doesn't really matter much" \
"because it will always be bound at physiological Ca."
call /kinetics/PP2B/CaM-Ca2-bind-CaNAB/notes LOAD \
"Based on Stemmer and Klee 1994 Biochem 33:6859-6866" \
"This model is actually a simplification of the detail they report." \
"In this model the Ca-binding affinity of CaM is not changed by " \
"binding to CaN." \
"Rates here come from a detailed-balance argument. The reference rate" \
"is for CaMCa4 binding to CaNAB. This rate should be 1/2500 of that."
call /kinetics/PP2B/CaMCa3-CaNAB/notes LOAD \
"Ca3.CaM.Ca4.CaNAB" \
"This is assumed to have the same enzymatic activity as the other" \
"Ca states of CaM bound to CaNAB. Hence I just put this into a summation" \
"with the other states and utilize  the sum for the enzymatic steps."
call /kinetics/PP2B/CaMCa2-CANAB/notes LOAD \
"Ca2.CaM.Ca4.CaNAB" \
"The CaM has only 2 calciums attached, but CaNAB has all 4." \
"This contributes equally to enzyme activity along with" \
"the Ca3 and Ca4 forms."
call /kinetics/PP2B/CaMCa4-CaNAB/notes LOAD \
"Ca4.CaM.Ca4.CaNAB. This form is fullly loaded with Ca. Its activity" \
"is assumed to be the same as the lower Ca-bound forms of CaM.Ca4.CaNAB." \
""
call /kinetics/PP2B/CaMCa3-bind-CaNAB/notes LOAD \
"Rates derived from the CaMCa4 binding to CaNAB-Ca4 step." \
"Due to detailed balance calculations taking the Ca affinity for CaM" \
"into account, this reaction should be 250 times slower. Close."
call /kinetics/PP2B/CaMCa4-bind-CaNAB/notes LOAD \
"This step is the starting point for calculating all the CaM-binding" \
"steps to CaNAB-Ca4. The calculation goes like this:" \
"From Stemmer and Klee 1994 Biochem 33 6859-6866 we have rates for" \
"Ca binding to CaM.Ca4.CaN." \
"From detailed balance (Kd must be 1 around a loop) we can set ratios of" \
"Kds for CaMCa3 binding to CaN, and CaM-Ca2 binding to CaN. Thus those" \
"rates can come once we know the Kd for the current reaction of" \
"CaMCa4 binding to CaN." \
"We'll ignore the Ca binding steps to CaM.Ca4.CaN since the reactions " \
"around the remaining part of the loop will settle pretty fast to the same" \
"levels." \
"Finally, we estimate the kf=0.001 here from a series of simulations" \
"matching the curves in Stemmer and Klee."
call /kinetics/PKA/notes LOAD \
"Protein kinase A. It has two regulatory and two catalytic subunits," \
"represented here as R2C2. Each regulatory subunit binds two cAMPs." \
"I also model an inhibitor of PKA which binds stoichiometrically and thus" \
"sharpens the response curve for PKA against cAMP." \
"General reference: Taylor et al Ann Rev Biochem 1990 59:971-1005" \
"Other references" \
"Ogreid and Doskeland 1983 Biochem 22:1686-1696 is a great, detailed paper." \
"Also: Ogreid and Doskeland 1982 FEBS Lett 150(1):161-166" \
"Ogreid et al 1983 JBC 258(2):1041-1049" \
"Robinson-Steiner and Corbin 1983 JBC 258(2):1032-1040" \
"Hasler et al 1992 FASEB J 6:2735-2741"
call /kinetics/PKA/R2C2/notes LOAD \
"This is the R2C2 complex, consisting of 2 catalytic (C)" \
"subunits, and the R-dimer. See Taylor et al Ann Rev Biochem" \
"1990 59:971-1005 for a review." \
"The Doskeland and Ogreid review is better for numbers." \
"Amount of PKA is about .5 uM."
call /kinetics/PKA/R2C2-cAMP/notes LOAD \
"One cAMP bound to site B1 on the regulatory subunits."
call /kinetics/PKA/cAMP-bind-site-B1/notes LOAD \
"Hasler et al FASEB J 6:2734-2741 1992 say Kd =1e-7M" \
"for type II, 5.6e-8 M for type I. " \
"" \
"Smith et al PNAS USA 78:3 1591-1595 1981 say that" \
"Ka1 is 2.1e7/M which gives a Kd of 47 nM," \
"Kan = 5e8/M or Kd of 2nM." \
"" \
"I prefer numbers from " \
"Ogreid and Doskeland Febs Lett 129:2 287-292 1981." \
"Their conditions are more physiological. They have figs" \
"suggesting time course of complete assoc is < 1 min."
call /kinetics/PKA/cAMP-bind-site-B2/notes LOAD \
"For now let us set this to the same Km (1e-7M) as" \
"site B1. This gives kf/kb = .7e-7M * 1e6 / (6e5^2) : 1/(6e5^2)" \
"= 2e-13:2.77e-12" \
""
call /kinetics/PKA/cAMP-bind-site-A1/notes LOAD \
"This site has a higher Kd for cAMP." \
"See Ogreid and Doskeland 1982 FEBS Lett 150:1 161-166"
call /kinetics/PKA/cAMP-bind-site-A2/notes LOAD \
"Cooperativity kicks in, now we have a low Kd for cAMP."
call /kinetics/PKA/R2C2-cAMP2/notes LOAD \
"One cAMP bound to each of the B sites on the regulatory subunits."
call /kinetics/PKA/R2C2-cAMP3/notes LOAD \
"3 cAMPs now bound."
call /kinetics/PKA/R2C2-cAMP4/notes LOAD \
"All the regulatory subunits now have cAMP bound. This state" \
"is ready to dissociate and to release the catalytic subunit."
call /kinetics/PKA/R2-cAMP4/notes LOAD \
"The regulatory subunit with 4 cAMPs but the catalytic subunit has been" \
"released."
call /kinetics/PKA/Release-C1/notes LOAD \
"The complex starts to dissociate and release the catalytic subunit C." \
"" \
"This has to be fast, as the activation of PKA by cAMP" \
"is also fast." \
""
call /kinetics/PKA/Release-C2/notes LOAD \
"Second catalytic subunit is now released."
call /kinetics/PKA/PKA-inhibitor/notes LOAD \
"About 25% of PKA C subunit is dissociated in resting cells without" \
"having any noticable activity." \
"Doskeland and Ogreid Int J biochem 13 pp1-19 suggest that this is" \
"because there is a corresponding amount of inhibitor protein."
call /kinetics/PKA/inhib-PKA/notes LOAD \
"See Doskeland and Ogreid Int J Biochem 13:1-19." \
"Not clear what the rates are, but the reaction has to be fast and it has" \
"to have a pretty high affinity. The exact values are not critical" \
"under these conditions."
call /kinetics/PKA/inhibited-PKA/notes LOAD \
"This is the inhibitor bound to PKA."
call /kinetics/AC/notes LOAD \
"The adenylyl cyclase module currently represents only two isoforms:" \
"AC1 and AC2. There are at least 8 forms of AC known:" \
"Pieroni et al 1993 Curr Op Neurobiol 3:345-351." \
"AC1 is stimulated by CaM, and AC2 by phosphorylation by PKC, in addition" \
"to the usual Gs stimulation." \
"A more recent thorough review is " \
"Defer et al 2000 Am J Physiol Renal Physiol 279:F400-F416" \
"This model does not incorporate effects such as GAP activity of the" \
"cyclases."
call /kinetics/AC/ATP/notes LOAD \
"ATP is present in all cells between 2 and 10 mM. See Lehninger."
call /kinetics/AC/AC1-CaM/notes LOAD \
"This state of AC1 is bound to Calmodulin and therefore activated." \
"Gs stimulates it but betagamma inhibits."
call /kinetics/AC/AC1-CaM/kenz/notes LOAD \
"Vmax is assumed to be the same as that for the Gs-stimulated form." \
"The rates are from: " \
"Smigel 1986 JBC 261(4):1976-1982 who has " \
"8.27 umol/min/mg with forskolin stimulated AC." \
"Tang et al JBC 266(13):8595-8603 have an almost identical Vmax" \
"of 8 umol/min/mg." \
"This comes to a Vmax of 18/sec." \
"The Km is pretty immaterial since the vast excess of" \
"ATP means that the enzyme will normally be saturated." \
"This is a pretty fast enzyme." \
"Note that the saturation of the enzyme means that the regulatory" \
"reactions have to involve the complex rather than the free enzyme."
call /kinetics/AC/AC1/notes LOAD \
"AC concentrations are tricky due to poor antibodies. I refer to an estimate" \
"from Jacobowitz, PhD Thesis, Mount Sinai School of Medicine" \
"around Pg 149 which estimates cyclase" \
"as 1/12600 of membrane protein. This gives a whole-cell conc of" \
"about 33 nM using assumptions of 2% of cell mass being membrane protein." \
"Defer et al 2000 Am J Physiol Renal Physiol 279:F400-F416 in a good review" \
"put AC1 and AC8 (which has similar properties)" \
"as among the highly expressed form of brain cyclase." \
"We therefore estimate its levels as a good fraction of the 33 nM," \
"at 20 nM."
call /kinetics/AC/CaM-bind-AC1/notes LOAD \
"Half-max at 20 nM CaM (Tang et al JBC 266:13 8595-8603 1991" \
"Assume a rapid CaM binding of 1/sec."
call /kinetics/AC/AC2*/notes LOAD \
"This is the phosphorylation-activated form of AC2."
call /kinetics/AC/AC2*/kenz/notes LOAD \
"The Vmax is scaled down to 7/sec from the Gs-stimulated form. This is" \
"constrained because we have a measure of basal activity" \
"due to basal phosphorylation by PKC. Two papers measure" \
"activation of AC2 by phosphorylation without Gs:" \
"Jacobowitz et al JBC 268(6):3829-3832 (Stim 3x) and" \
"Yoshimura and Cooper 1993 JBC 26(7):4604-4607 (Stim 9x)." \
"The conditions are somewhat different in the two cases." \
"" \
"The reference maximally stimulated Vmax is 18/sec from" \
"Smigel 1986 JBC 261(4):1976-1982 who has " \
"8.27 umol/min/mg with forskolin stimulated AC." \
"Tang et al JBC 266(13):8595-8603 have an almost identical Vmax" \
"of 8 umol/min/mg." \
"This comes to a Vmax of 18/sec." \
"The Km is pretty immaterial since the vast excess of" \
"ATP means that the enzyme will normally be saturated." \
"This is a pretty fast enzyme." \
"Note that the saturation of the enzyme means that the regulatory" \
"reactions have to involve the complex rather than the free enzyme."
call /kinetics/AC/AC2-Gs/notes LOAD \
"This is the generic Gs-Stimulated form of AC2" \
""
call /kinetics/AC/AC2-Gs/kenz/notes LOAD \
"Vmax is assumed to be the same as for AC1. This is consistent since" \
"there is a good match between the mixture of ACs tested by" \
"Smigel 1986 JBC 261(4):1976-1982 who has " \
"8.27 umol/min/mg with forskolin stimulated AC." \
"Tang et al JBC 266(13):8595-8603 have an almost identical Vmax" \
"of 8 umol/min/mg for AC1." \
"This comes to a Vmax of 18/sec." \
"The Km is pretty immaterial since the vast excess of" \
"ATP means that the enzyme will normally be saturated." \
"This is a pretty fast enzyme." \
"Note that the saturation of the enzyme means that the regulatory" \
"reactions have to involve the complex rather than the free enzyme."
call /kinetics/AC/AC2/notes LOAD \
"AC concentrations are tricky due to poor antibodies. I refer to an estimate" \
"from Jacobowitz, PhD Thesis, Mount Sinai School of Medicine" \
"around Pg 149 which estimates cyclase" \
"as 1/12600 of membrane protein. This gives a whole-cell conc of" \
"about 33 nM using assumptions of 2% of cell mass being membrane protein." \
"Defer et al 2000 Am J Physiol Renal Physiol 279:F400-F416 in a good review" \
"put AC2 among the highly expressed form of brain cyclase." \
"We therefore estimate its levels as a good fraction of the 33 nM," \
"at 15 nM. This actually adds up to a little more than 33, but it is well" \
"within error estimates."
call /kinetics/AC/dephosph-AC2/notes LOAD \
"Rate constrained by balancing levels of phosphorylated form, especially" \
"given resting PKC levels."
call /kinetics/AC/AC1-Gs/notes LOAD \
"This is the generic Gs-Stimulated state of AC1." \
"Note that the enzyme is normally saturated, so all reactions " \
"involving AC1-Gs actually relate to the enzyme-substrate complex."
call /kinetics/AC/AC1-Gs/kenz/notes LOAD \
"Vmax is from " \
"Smigel 1986 JBC 261(4):1976-1982 who has " \
"8.27 umol/min/mg with forskolin stimulated AC." \
"Tang et al JBC 266(13):8595-8603 have an almost identical Vmax" \
"of 8 umol/min/mg." \
"This comes to a Vmax of 18/sec." \
"The Km is pretty immaterial since the vast excess of" \
"ATP means that the enzyme will normally be saturated." \
"This is a pretty fast enzyme." \
"Note that the saturation of the enzyme means that the regulatory" \
"reactions have to involve the complex rather than the free enzyme."
call /kinetics/AC/Gs-bind-AC2/notes LOAD \
"Half-max at around 3nM = kb/kf from fig 5 in " \
"Feinstein et al PNAS USA 88 10173-10177 1991" \
"kf = kb/1800 = 5.56e-4 kb" \
"Ofer Jacobowitz's thesis data indicates it is more like 2 nM." \
"Jacobowitz, PhD Thesis, Mount Sinai School of Medicine." \
""
call /kinetics/AC/Gs-bind-AC1/notes LOAD \
"Half-max 8nM from Tang et al JBC266:13 8595-8603" \
"kb/kf = 8 nM = 4800#/cell " \
"Also assume rapid binding of 1/sec."
call /kinetics/AC/AMP/notes LOAD \
"AMP is a tightly regulated metabolite, so here we simply buffer" \
"it to its resting value. The value doesn't really matter to any" \
"of the calculations since it acts like a one-way sink."
call /kinetics/AC/AC2*-Gs/notes LOAD \
"This is the form activated synergistically by phosphorylation as" \
"well as Gs binding."
call /kinetics/AC/AC2*-Gs/kenz/notes LOAD \
"The Km is higher here but it is still well below the level of ATP so the" \
"enzyme remains saturated." \
"The Vmax is 3x higher than the reference forskolin stimulated form." \
"This scale factor is a compromise between the 2x rise reported by" \
"Jacobowitz et al JBC 268(6): 3829-3832 and the 9x rise reported by " \
"Yoshimura and Cooper 1993 JBC 268(7):4604-4607." \
"" \
"The reference Vmax is from " \
"Smigel 1986 JBC 261(4):1976-1982 who has " \
"8.27 umol/min/mg with forskolin stimulated AC." \
"Tang et al JBC 266(13):8595-8603 have an almost identical Vmax" \
"of 8 umol/min/mg." \
"This comes to a Vmax of 18/sec." \
"The Km is pretty immaterial since the vast excess of" \
"ATP means that the enzyme will normally be saturated." \
"This is a pretty fast enzyme." \
"Note that the saturation of the enzyme means that the regulatory" \
"reactions have to involve the complex rather than the free enzyme."
call /kinetics/AC/Gs-bind-AC2*/notes LOAD \
"Various references:" \
"Jacobowitz et al JBC 268(6):3829-3892 show that AC2 has" \
"a 2x rise in basal activation on phosphorylation," \
"and a 2x rise in forskolin stimulated activation." \
"" \
"Yoshimura and Cooper JBC 1993 268(7):4604-4607 say that" \
"type II is stimulated 9x over basal. " \
"" \
"Lustig et al 1993 JBC 268(19):13900-13905 syow a 2x activation" \
"by PDBu, and the Gs stimulated response is increased 2x-4x by" \
"PDBu." \
"" \
"To match all these results with the binding of the unphosphorylated form" \
"we use a Kd of 1.2 nM here as compared with the Kd of 2 nM for the" \
"unphosphorylated reaction."
call /kinetics/AC/cAMP-PDE/notes LOAD \
"The levels of the PDE are not known at this time. However," \
"enough" \
"kinetic info and info about steady-state levels of cAMP" \
"etc are around" \
"to make it possible to estimate this."
call /kinetics/AC/cAMP-PDE/PDE/notes LOAD \
"Best rates are from Conti et al Biochem 34 7979-7987 1995." \
"Though these are for the Sertoli cell form, it looks like they carry" \
"nicely into alternatively spliced brain form. See Sette et al" \
"JBC 269:28 18271-18274" \
"Borisy et al J Neurosci 12(3):915-923 also have estimates with a Km of 40 uM" \
"specifically for brain PDE. The Vmax is very low and it looks like the purification is not good." \
"" \
"Combining this with data from the Conti paper and the Sette paper," \
"it looks like a fair compromise is " \
"Km ~20 uM, Vmax est ~ 10 umol/min/mg or about 10/sec." \
""
call /kinetics/AC/cAMP-PDE*/notes LOAD \
"This form has about 2X activity as plain PDE. See Sette et al JBC 269:28" \
"18271-18274 1994."
call /kinetics/AC/cAMP-PDE*/PDE*/notes LOAD \
"This form has about twice the activity of the unphosphorylated form. See" \
"Sette et al JBC 269:28 18271-18274 1994." \
"We'll ignore cGMP effects for now. The Vmax is therefore scaled to twice" \
"the value used in the unstimulated PDE enzyme."
call /kinetics/AC/dephosph-PDE/notes LOAD \
"The rates for this are poorly constrained. In adipocytes (probably a" \
"different PDE) the dephosphorylation is complete within 15 min, but" \
"there are no intermediate time points so it could be much faster. Identity" \
"of phosphatase is still unknown."
call /kinetics/AC/PDE1/notes LOAD \
"CaM-Dependent PDE. 66KDa" \
"Borisy et al J Neurosci 12(3):915-923" \
"About 0.6% of membrane protein. so estimate 2 uM as " \
"conc in brain." \
"Also see Conti et al Adv Sec Mess Phosphoprotein Res 1992 25:87-99"
call /kinetics/AC/PDE1/PDE1/notes LOAD \
"From Borisy et al J Neurosci 12(3):915-923 the basal rate goes up 6x" \
"with Ca stimulation." \
"Km = 40. The stimulated Vmax in this paper is very low. But" \
"Conti et al 1994 Biochem 34:7979-7987 report a 2000x purified form which" \
"has a stimulated Vmax of 10 umol/min/mg or about 10/sec (given that the" \
"mol wt is around 65KDa.)." \
"Here we use a Vmax = 1/6 of the CaM stim form." \
""
call /kinetics/AC/CaM.PDE1/notes LOAD \
"PDE1 is the 66 KDa form which binds CaM." \
"Borisy et al J Neurosci 12(3):915-923 report a 6x stimulation with calcium."
call /kinetics/AC/CaM.PDE1/CaM.PDE1/notes LOAD \
"From Conti et al 1995 Biochem 34:7979-7987 the stimulated Vmax is" \
" ~10umol/min/mg in presence of lots of CaM. This works out to about" \
"10/sec." \
"Affinity is low, 40 uM." \
""
call /kinetics/AC/CaM_bind_PDE1/notes LOAD \
"Borisy et al J Neurosci 12(3):915-923" \
"For olf epithelium PDE1, affinity is 7 nM CaM and about 2 uM Ca which" \
"is consistent with it binding Ca4.CaM at 7 nM. Assume same for brain." \
"Reaction should be pretty fast. Assume kb = 5/sec." \
""
call /kinetics/Gs-alpha/notes LOAD \
"This is actualy GTP.Gs_alpha, the active form of Gs." \
"Resting Gs-alpha is nearly zero. "
call /kinetics/remove_glu/notes LOAD \
"This reaction doubles for arrival as well as removal of glu from" \
"the synapse." \
"Assume tau for removal of glu is ~1 msec. We know that diffusion" \
"time for arrival of glu from presynaptic side is < 50 usec." \
"Most of the actual synaptic delay has to do with binding to the" \
"receptors."
call /kinetics/synapse/notes LOAD \
"A pool representing the presynaptic terminal and release of " \
"glutamate. It is controlled by" \
"the temporal pattern of the synaptic input."
call /kinetics/Ca_tab/notes LOAD \
"Set up with a single Ca pulse for a train of 100 stim " \
"in 1 sec."
call /kinetics/CaRegulation/notes LOAD \
"This simple implementation of Ca regulation includes three compartments:" \
"the extracellular, the intracellular, and the Ca stores. Pumps maintain" \
"the Ca levels in cytoplasm (pumping out to the extracellular space and" \
"into the stores). Leak channels from the stores and extracellular space" \
"balance it out. Finally, the IP3 receptor and the capacitive entry " \
"channel respond to stimuli of various kinds." \
"One clear direction for further work is to incorporate various calcium" \
"buffering proteins such as calsequestrin into the model." \
"Primary reference is from the book" \
"Receptors: Models for binding, trafficking and signaling, by" \
"Lauffenburger and Linderman, OUP, 1993, Ch 5, around pg 200. There" \
"is extensive reference to a submitted paper by Mahama and Linderman, whose" \
"published version appears to be " \
"Mahama and Linderman 1994 Biophys J 67(3):1345-1357" \
"This model is a little artificial on the IP3R kinetics and does not include" \
"the Ca influence on IP3R."
call /kinetics/CaRegulation/CaTraspATPase/notes LOAD \
"kCa3 = 2 * Ca transporter rate since each step has 2 Ca++. " \
"= 0.5 uM/sec from Lauffenburger and Linderman 1993 Receptors pg 200." \
"The amount of the activated transporter is about 0.01 uM = 6e3 #." \
"from runs." \
"So  0.01uM * kf * 2 = 0.5 uM/sec (no back reaction)" \
"so kf = 25, kb = 0" \
"Alternatively, 6e3 * kf = 0.25 * 6e5, giving the same kf"
call /kinetics/CaRegulation/Ca-sequester/notes LOAD \
"This is the sequestered Calcium pool." \
"The vol is 0.16 * the vol of the cell as a whole." \
"This pool should really equilibrate with a highly buffered pool of" \
"Calcium, but that is not present in this version of the model." \
""
call /kinetics/CaRegulation/Ca-leak-to-cytoplasm/notes LOAD \
"This pool represents the channels which leak Ca into the cytoplasm." \
"It is a probably a composite of various channels depending on" \
"cell type. Membrane potential will obviously affect the leak amount," \
"but that is not considered." \
"The amounts and total flux are constrained by the need to balance the" \
"Ca flux and keep basal Ca levels around 80 nM."
call /kinetics/CaRegulation/Ca-leak-to-cytoplasm/Ca-leak-chan/notes LOAD \
"This ch"
call /kinetics/CaRegulation/CaTransp-2Ca/notes LOAD \
"This is equivalent to the enzyme-substrate complex." \
"2 Ca are bound to the transporter. The ATP is ignored."
call /kinetics/CaRegulation/CaTransp/notes LOAD \
"The calcium transporter levels are constrained by the resting levels" \
"of Ca in the cell. The rate of Ca" \
"sequestration depends on the amount of this pool." \
""
call /kinetics/CaRegulation/Ca-bind-to-Transp/notes LOAD \
"Rates from Lauffenberger and Linderman 1993 Receptors pg 200." \
"Kd = KCa2 = 0.2 uM." \
""
call /kinetics/CaRegulation/IP3R/notes LOAD \
"The number of the IP3Rs in the cell is present only implicitly in the" \
"model, and is lumped in with the total permeability of the IP3R pool." \
"The latter term is constrained by the height of the Ca transient." \
""
call /kinetics/CaRegulation/IP3Rbind/notes LOAD \
"Based on Lauffenburger and Linderman 1993 Receptors page 200. " \
"The binding of IP3 in this reaction has a Hill coeff of 3. The eqns of " \
"Mahama and Linderman (cited in the book as 1993 a)" \
"are equivalent to the binding all occurring in a single step, so that is how" \
"I am doing it in this version." \
"Their Ki1 is 0.07 uM." \
"Lots of other data sources:" \
"Ramos-Franco et al 1998 Biophys J 75:834-839 have Ca sensitivity " \
"curves. At 250 nM free Ca, the EC50 for type 1 is 58 nM and" \
" type 2 is 194 nM. Type 3 would be about 2 uM according to " \
"Newton et al 1994 JBC 268(46):28613-28619" \
"For the purposes of this model we use a Kd of 2.7 uM which is high but" \
"may be OK at low calcium. The details of Ca interaction with the IP3R" \
"are not included in this model." \
""
call /kinetics/CaRegulation/IP3R*/notes LOAD \
"This is the ligand-bound form of the IP3 receptor. " \
""
call /kinetics/CaRegulation/IP3R*/IP3chan/notes LOAD \
"The max flow through this channel (assuming all open) is" \
"kCa1 = 0.1 sec^-1 in the M&L model. " \
"kCa1 = #IP3Rtot * permeability, and we have assumed #IP3Rtot = 1e4." \
"dconc = perm * concgrad * #chan / vol = 0.1 * concgrad" \
"so perm = 0.1 * vol / #chan = 0.1 * 6e5 / 1e5 = 0.6" \
"perm = 0.1 * 96000 / 1e4 = 9.6e-1" \
"Try 20 X to get reasonable response" \
"13 Oct 2k: Raised 10x to 200."
call /kinetics/CaRegulation/CaEPump/notes LOAD \
"The calcium electrogenic pump." \
"See McBurney and Neering 1987 TINS 10(4):164-169" \
"We treat the pump as a simple Michaelis-Menten enzyme." \
"Levels are constrained tightly by the need to keep resting Ca levels" \
"at about 80 nM."
call /kinetics/CaRegulation/CaEPump/Ca-pump-out/notes LOAD \
"From McBurney and Neering TINS 10(4) 164-169 1987. We are using the" \
"high-affinity pump here," \
"Their numbers exceed M&L so I am reducing" \
"the rates by 10X. Need to check." \
"k1 = 3e-3, k2 = 288, k3 = 72, n = 1000." \
"" \
"This comes to a Km of 0.2 for Ca, and a Vmax of 72."
call /kinetics/CaRegulation/Ca-ext/notes LOAD \
"Extracell Ca conc = 4 mM" \
"Extracell vol assumed 100 X cell vol" \
"It is kept buffered anyway for the puroposes of the model," \
"so the concentration won't change."
call /kinetics/CaRegulation/Ca-leak-from-extracell/notes LOAD \
"This represents the pool of Ca leak channels." \
"The concentration gradient is so large that this pool only needs a small " \
"number of molecules." \
"For an equilibrium at 0.1 uM we need flow of 36e3/sec. " \
"With a permeability of 0.01 and" \
"a concentration gradient of 4mM->0.1 uM (4e4) we get" \
"flux = N * perm * grad => N = 36e3 / (1e-2 * 4e3) = 900" \
"if flux = 20e3, N =500, which is what we use. This works out to " \
"a concentration of 0.83 nM." \
""
call /kinetics/CaRegulation/Ca-leak-from-extracell/Ca-leak-chan/notes LOAD \
"This ch"
call /kinetics/CaRegulation/capacitive_Ca_entry*/notes LOAD \
"This mechanism has taken a while to be more tightly confirmed as" \
"probably being the TRP channel." \
"In this model the channel is implemented to match" \
" experimental observations about capacitive " \
"Ca entry. Levels are set by two constraints: the resting Ca levels, and" \
"the height of the response to IP3." \
""
call /kinetics/CaRegulation/capacitive_Ca_entry*/Cap_entry_chan/notes LOAD \
"13 Oct 2000: Scaled up perm 2x to 0.01 to get larger" \
"Ca responses to IP3."
call /kinetics/CaRegulation/inactivate_cap_Ca/notes LOAD \
"The Kd is set to about 3 uM,  so that at resting " \
"Ca the capacitive Ca entry is almost blocked." \
"A 2nd order response makes the response steep." \
""
call /kinetics/CaRegulation/inact_cap_entry/notes LOAD \
"This represents the portion of the capacitive-Ca entry channel which is" \
"blocked when there is lots of Ca sequestered in the stores."
call /kinetics/Ca_intracell/notes LOAD \
"This is the pool representing intracellular calcium." \
"Resting levels are around 80 nM, but this is subject to all" \
"sorts of influxes and pumps."
call /kinetics/Ca/notes LOAD \
"This calcium pool is treated as being buffered to a" \
"steady 0.08 uM, which is the resting level. "
call /kinetics/IP3/notes LOAD \
"Peak IP3 is ~ 15 uM, basal ~ 0.2 uM."
call /kinetics/PIP2/notes LOAD \
"PIP2 is a bit troublesome in this model. Its level is well below what" \
"it should be based on more recent data. This value is kept in this" \
"model to correspond to the Km used in the enzymes. A scale factor" \
"of 5-10 in both terms would cancel out but improve the parameter estimate."
call /kinetics/doqcsinfo/notes LOAD \
"This model is an annotated version of the synaptic signaling network.<br>The primary reference is <a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888852&dopt=Abstract>Bhalla US and Iyengar R. Science (1999) 283(5400):381-7</a> but several of the model pathways have been updated."
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