//  DOQCS :http://doqcs.ncbs.res.in/ 
//  Accession Name = MAPK_network_2003 
//  Accession Number = 50 
//  Pathway Name = CaMKII 
//  Pathway Number = 216 
//  Transcriber = Upinder S. Bhalla, NCBS 
//  Developer = Upinder S. Bhalla, NCBS 
//  Species = Generic mammalian 
//  Tissue =  Brain - Neuronal 
//  Cell Compartment = Synapse 
//  Notes =  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 enzs look a terrible mess. Actually it is just 3 reactions for diff sites, by 4 states of CaMKII, defined by the phosph state.
 
//genesis
// kkit Version 11 flat dumpfile
 
// Saved on Tue Dec 13 12:09:20 2005
 
include kkit {argv 1}
 
FASTDT = 0.0001
SIMDT = 0.005
CONTROLDT = 10
PLOTDT = 10
MAXTIME = 4000
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 6 15 0
simundump group /kinetics/PKC 0 blue black x 0 1 "" defaultfile \
  /home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 6 4 0
simundump kpool /kinetics/PKC/PKC-Ca 0 0 3.7208e-17 3.7208e-17 2.2325e-11 \
  2.2325e-11 0 0 6e+05 0 /kinetics/geometry red black -4 1 0
simundump kreac /kinetics/PKC/PKC-act-by-Ca 0 1e-06 0.5 "" white blue -4 -2 0
simundump kreac /kinetics/PKC/PKC-act-by-DAG 0 1.3333e-08 8.6348 "" white \
  blue 4 -2 0
simundump kreac /kinetics/PKC/PKC-Ca-to-memb 0 1.2705 3.5026 "" white blue -4 \
  4 0
simundump kreac /kinetics/PKC/PKC-DAG-to-memb 0 1 0.1 "" white blue 4 4 0
simundump kreac /kinetics/PKC/PKC-act-by-Ca-AA 0 2e-09 0.1 "" white blue -2 4 \
  0
simundump kreac /kinetics/PKC/PKC-act-by-DAG-AA 0 2 0.2 "" white blue 2 4 0
simundump kpool /kinetics/PKC/PKC-DAG-AA* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry cyan blue 2 7 0
simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry orange blue -2 7 0
simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry pink blue -4 7 0
simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry yellow blue 4 7 0
simundump kpool /kinetics/PKC/PKC-basal* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry pink blue -6 7 0
simundump kreac /kinetics/PKC/PKC-basal-act 0 1 50 "" white blue -6 -2 0
simundump kpool /kinetics/PKC/PKC-AA* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry cyan blue 0 7 0
simundump kreac /kinetics/PKC/PKC-act-by-AA 0 2e-10 0.1 "" white blue -2 -2 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 white blue 4 1 0
simundump kreac /kinetics/PKC/PKC-n-DAG 0 1e-09 0.1 "" white blue 0 -2 0
simundump kpool /kinetics/PKC/PKC-DAG 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry white blue 0 1 0
simundump kreac /kinetics/PKC/PKC-n-DAG-AA 0 3e-08 2 "" white blue 2 -2 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 white blue 2 1 0
simundump kpool /kinetics/PKC/PKC-cytosolic 0 0 1 1 6e+05 6e+05 0 0 6e+05 0 \
  /kinetics/geometry white blue -2 -5 0
simundump kpool /kinetics/PKC/degraded-PKC 0 0 0 0 0 0 0 0 6e+05 4 \
  /kinetics/geometry 27 blue -1 13 0
simundump kpool /kinetics/PKC/PKC-RNA 0 0 1 1 6e+05 6e+05 0 0 6e+05 4 \
  /kinetics/geometry 23 blue -6 -5 0
simundump kreac /kinetics/PKC/PKC-synthesis 0 4.1666e-06 0 "" white blue -4 \
  -8 0
simundump kreac /kinetics/PKC/PKC-downreg_basal 0 4.63e-05 0 "" white blue -6 \
  10 0
simundump kreac /kinetics/PKC/PKC-Ca_downreg 0 4.63e-05 0 "" white blue -4 10 \
  0
simundump kreac /kinetics/PKC/PKC-DAG_downreg 0 4.63e-05 0 "" white blue 4 10 \
  0
simundump kreac /kinetics/PKC/PKC-Ca-AA_downreg 0 4.63e-05 0 "" white blue -2 \
  10 0
simundump kreac /kinetics/PKC/PKC-DAG-AA_downreg 0 4.63e-05 0 "" white blue 2 \
  10 0
simundump kreac /kinetics/PKC/PKC-AA_downreg 0 4.63e-05 0 "" white blue 0 10 \
  0
simundump kpool /kinetics/PKC/PKC-active 0 0 0 0 0 0 0 0 6e+05 2 \
  /kinetics/geometry yellow blue 6 10 0
simundump kenz /kinetics/PKC/PKC-active/PKC-enzyme-activity 1 0 0 0 0 6e+05 \
  1e-05 16 4 0 0 "" red yellow "" 6 11 0
simundump kpool /kinetics/PKC/Ca 1 0 0.08 0.08 48000 48000 0 0 6e+05 0 \
  /kinetics/geometry red blue -4 -5 0
simundump kpool /kinetics/PKC/AA 0 0 5.5 5.5 3.3e+06 3.3e+06 0 0 6e+05 0 \
  /kinetics/geometry darkgreen blue 0 -5 0
simundump kpool /kinetics/PKC/DAG 1 0 11.66 11.66 6.996e+06 6.996e+06 0 0 \
  6e+05 0 /kinetics/geometry green blue 2 -5 0
simundump kpool /kinetics/PKC/PKC-substrate 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry blue blue 4 13 0
simundump kpool /kinetics/PKC/PKC-substrate* 0 0 0 0 0 0 0 0 6e+05 0 \
  /kinetics/geometry 60 blue 6 13 0
simundump doqcsinfo /kinetics/doqcsinfo 0 pdb216.g CaMKII pathway \
  "Upinder S. Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "citation here" \
  "Generic Mammalian" "Brain - Neuronal" Synapse Qualitative \
  "<a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15298883&query_hl=11>Bhalla US Biophys J. 2004 Aug;87(2):745-53</a> ( peer-reviewed publication )" \
  "Exact GENESIS implementation" "Approximates original data " 4 15 0
simundump xgraph /graphs/conc1 0 0 4000 0 51.483 0
simundump xgraph /graphs/conc2 0 0 4000 0 0.29607 0
simundump xplot /graphs/conc1/PKC-active.Co 3 524288 \
  "delete_plot.w <s> <d>; edit_plot.D <w>" yellow 0 0 1
simundump xplot /graphs/conc1/nuc_MAPK*.Co 3 524288 \
  "delete_plot.w <s> <d>; edit_plot.D <w>" 47 0 0 1
simundump xplot /graphs/conc2/PDGFR.Co 3 524288 \
  "delete_plot.w <s> <d>; edit_plot.D <w>" red 0 0 1
simundump xplot /graphs/conc2/PDGF.Co 3 524288 \
  "delete_plot.w <s> <d>; edit_plot.D <w>" red 0 0 1
simundump xgraph /moregraphs/conc3 0 0 13040 0 1 0
simundump xgraph /moregraphs/conc4 0 0 13040 0 1 0
simundump xcoredraw /edit/draw 0 -7.2 8.8 -6.25 18.75
simundump xtree /edit/draw/tree 0 \
  /kinetics/#[],/kinetics/#[]/#[],/kinetics/#[]/#[]/#[][TYPE!=proto],/kinetics/#[]/#[]/#[][TYPE!=linkinfo]/##[] \
  "edit_elm.D <v>; drag_from_edit.w <d> <S> <x> <y> <z>" auto 0.6
simundump xtext /file/notes 0 1
xtextload /file/notes \
"PKC downreg model. Assumes" \
"6 hour downreg time when kinase" \
"is fully active." \
"Based on pkc47.g" \
""
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/PKC/Ca /kinetics/PKC/PKC-act-by-Ca SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca /kinetics/PKC/PKC-act-by-Ca PRODUCT n 
addmsg /kinetics/PKC/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/PKC/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 
addmsg /kinetics/PKC/PKC-DAG-AA* /kinetics/PKC/PKC-act-by-DAG-AA PRODUCT n 
addmsg /kinetics/PKC/PKC-DAG-AA /kinetics/PKC/PKC-act-by-DAG-AA SUBSTRATE n 
addmsg /kinetics/PKC/PKC-act-by-DAG-AA /kinetics/PKC/PKC-DAG-AA* REAC B A 
addmsg /kinetics/PKC/PKC-DAG-AA_downreg /kinetics/PKC/PKC-DAG-AA* REAC A B 
addmsg /kinetics/PKC/PKC-act-by-Ca-AA /kinetics/PKC/PKC-Ca-AA* REAC B A 
addmsg /kinetics/PKC/PKC-Ca-AA_downreg /kinetics/PKC/PKC-Ca-AA* REAC A B 
addmsg /kinetics/PKC/PKC-Ca-to-memb /kinetics/PKC/PKC-Ca-memb* REAC B A 
addmsg /kinetics/PKC/PKC-Ca_downreg /kinetics/PKC/PKC-Ca-memb* REAC A B 
addmsg /kinetics/PKC/PKC-DAG-to-memb /kinetics/PKC/PKC-DAG-memb* REAC B A 
addmsg /kinetics/PKC/PKC-DAG_downreg /kinetics/PKC/PKC-DAG-memb* REAC A B 
addmsg /kinetics/PKC/PKC-basal-act /kinetics/PKC/PKC-basal* REAC B A 
addmsg /kinetics/PKC/PKC-downreg_basal /kinetics/PKC/PKC-basal* REAC A B 
addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-basal-act SUBSTRATE n 
addmsg /kinetics/PKC/PKC-basal* /kinetics/PKC/PKC-basal-act PRODUCT n 
addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/PKC/PKC-AA* REAC B A 
addmsg /kinetics/PKC/PKC-AA_downreg /kinetics/PKC/PKC-AA* REAC A B 
addmsg /kinetics/PKC/AA /kinetics/PKC/PKC-act-by-AA SUBSTRATE n 
addmsg /kinetics/PKC/PKC-AA* /kinetics/PKC/PKC-act-by-AA PRODUCT n 
addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-act-by-AA SUBSTRATE n 
addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/PKC/PKC-Ca-DAG REAC B A 
addmsg /kinetics/PKC/PKC-DAG-to-memb /kinetics/PKC/PKC-Ca-DAG REAC A B 
addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-n-DAG SUBSTRATE n 
addmsg /kinetics/PKC/DAG /kinetics/PKC/PKC-n-DAG SUBSTRATE n 
addmsg /kinetics/PKC/PKC-DAG /kinetics/PKC/PKC-n-DAG PRODUCT n 
addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/PKC-DAG REAC B A 
addmsg /kinetics/PKC/PKC-n-DAG-AA /kinetics/PKC/PKC-DAG REAC A B 
addmsg /kinetics/PKC/PKC-DAG /kinetics/PKC/PKC-n-DAG-AA SUBSTRATE n 
addmsg /kinetics/PKC/AA /kinetics/PKC/PKC-n-DAG-AA SUBSTRATE n 
addmsg /kinetics/PKC/PKC-DAG-AA /kinetics/PKC/PKC-n-DAG-AA PRODUCT n 
addmsg /kinetics/PKC/PKC-n-DAG-AA /kinetics/PKC/PKC-DAG-AA REAC B A 
addmsg /kinetics/PKC/PKC-act-by-DAG-AA /kinetics/PKC/PKC-DAG-AA REAC A B 
addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/PKC-cytosolic REAC A B 
addmsg /kinetics/PKC/PKC-basal-act /kinetics/PKC/PKC-cytosolic REAC A B 
addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/PKC/PKC-cytosolic REAC A B 
addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/PKC-cytosolic REAC A B 
addmsg /kinetics/PKC/PKC-synthesis /kinetics/PKC/PKC-cytosolic REAC B A 
addmsg /kinetics/PKC/PKC-downreg_basal /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-Ca_downreg /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-DAG_downreg /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-Ca-AA_downreg /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-AA_downreg /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-DAG-AA_downreg /kinetics/PKC/degraded-PKC REAC B A 
addmsg /kinetics/PKC/PKC-synthesis /kinetics/PKC/PKC-RNA REAC A B 
addmsg /kinetics/PKC/PKC-RNA /kinetics/PKC/PKC-synthesis SUBSTRATE n 
addmsg /kinetics/PKC/PKC-cytosolic /kinetics/PKC/PKC-synthesis PRODUCT n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-downreg_basal PRODUCT n 
addmsg /kinetics/PKC/PKC-basal* /kinetics/PKC/PKC-downreg_basal SUBSTRATE n 
addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC/PKC-Ca_downreg SUBSTRATE n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-Ca_downreg PRODUCT n 
addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC/PKC-DAG_downreg SUBSTRATE n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-DAG_downreg PRODUCT n 
addmsg /kinetics/PKC/PKC-Ca-AA* /kinetics/PKC/PKC-Ca-AA_downreg SUBSTRATE n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-Ca-AA_downreg PRODUCT n 
addmsg /kinetics/PKC/PKC-DAG-AA* /kinetics/PKC/PKC-DAG-AA_downreg SUBSTRATE n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-DAG-AA_downreg PRODUCT n 
addmsg /kinetics/PKC/PKC-AA* /kinetics/PKC/PKC-AA_downreg SUBSTRATE n 
addmsg /kinetics/PKC/degraded-PKC /kinetics/PKC/PKC-AA_downreg PRODUCT n 
addmsg /kinetics/PKC/PKC-DAG-AA* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-Ca-memb* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-Ca-AA* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-DAG-memb* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-basal* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-AA* /kinetics/PKC/PKC-active SUMTOTAL n nInit 
addmsg /kinetics/PKC/PKC-active/PKC-enzyme-activity /kinetics/PKC/PKC-active REAC eA B 
addmsg /kinetics/PKC/PKC-active /kinetics/PKC/PKC-active/PKC-enzyme-activity ENZYME n 
addmsg /kinetics/PKC/PKC-substrate /kinetics/PKC/PKC-active/PKC-enzyme-activity SUBSTRATE n 
addmsg /kinetics/PKC/PKC-act-by-Ca /kinetics/PKC/Ca REAC A B 
addmsg /kinetics/PKC/PKC-act-by-Ca-AA /kinetics/PKC/AA REAC A B 
addmsg /kinetics/PKC/PKC-act-by-AA /kinetics/PKC/AA REAC A B 
addmsg /kinetics/PKC/PKC-n-DAG-AA /kinetics/PKC/AA REAC A B 
addmsg /kinetics/PKC/PKC-act-by-DAG /kinetics/PKC/DAG REAC A B 
addmsg /kinetics/PKC/PKC-n-DAG /kinetics/PKC/DAG REAC A B 
addmsg /kinetics/PKC/PKC-active/PKC-enzyme-activity /kinetics/PKC/PKC-substrate REAC sA B 
addmsg /kinetics/PKC/PKC-active/PKC-enzyme-activity /kinetics/PKC/PKC-substrate* MM_PRD pA 
addmsg /kinetics/PKC/PKC-active /graphs/conc1/PKC-active.Co PLOT Co *PKC-active.Co *yellow 
enddump
// End of dump

call /kinetics/PKC/notes LOAD \
"This enzyme represents an averaged PKC activity, most closely" \
"based on the alpha, beta, and gamma forms."
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 typicmpdmyy 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. Mechanisticmpdmyy" \
"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/PKC/degraded-PKC/notes LOAD \
"This represents the ubiquitination and eventual removal of the PKC." \
"See Lu et al 1998 Mol Cell Biol 18(2):839-845"
call /kinetics/PKC/PKC-RNA/notes LOAD \
"Just a unity concentration for convenience. The rate limiting" \
"step is the PKC-synthesis reaction."
call /kinetics/PKC/PKC-synthesis/notes LOAD \
"This rate is set up to balance the removal of PKC at resting PKC" \
"levels of about 0.09 uM."
call /kinetics/PKC/PKC-downreg_basal/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/PKC-Ca_downreg/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/PKC-DAG_downreg/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/PKC-Ca-AA_downreg/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/PKC-DAG-AA_downreg/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/PKC-AA_downreg/notes LOAD \
"Typical rate for downreg is 6 hours. The downregulation appears to" \
"occur by a suicide mechanism in which the active PKC gets ubiquinated" \
"and degraded. The reference for this is" \
"Lu Z, Liu D, Hornia A, Devonish W, Pagana M and Foster DA 1998" \
"Mol Cell Biol 18(2):839-845." \
"" \
" I assume all activated forms of PKC downreg at the same rate."
call /kinetics/PKC/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/PKC-active/PKC-enzyme-activity/notes LOAD \
"Rate consts from Chen et al Biochem 32, 1032 (1993)" \
"Generic PKC rates."
call /kinetics/PKC/Ca/notes LOAD \
"This calcium pool is treated as being buffered to a" \
"steady 0.08 uM, which is the resting level. "
call /kinetics/PKC/AA/notes LOAD \
"Arachidonic Acid. This messenger diffuses through membranes" \
"as well as cytosolically, has been suggested as a possible" \
"retrograde messenger at synapses. " \
"Based on simulations the AA settles to around 5.5 uM under" \
"resting conditions."
call /kinetics/PKC/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/PKC/PKC-substrate/notes LOAD \
"This molecule represents a generic PKC substrate." \
""
call /kinetics/PKC/PKC-substrate*/notes LOAD \
"This is the phosphorylated form of a generic PKC substrate."
call /kinetics/doqcsinfo/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 enzs look a terrible mess. Actually it is just 3 reactions for diff sites, by 4 states of CaMKII, defined by the phosph state."
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