// DOQCS : http://doqcs.ncbs.res.in/
// Accession Name = PKC_turnover
// Accession Number = 26
// Transcriber = Upinder S. Bhalla, NCBS
// Developer = Upinder S. Bhalla, NCBS
// Species = Generic mammalian
// Tissue = Brain - Neuronal
// Cell Compartment = Cell membrane +Cytosol
// Notes = This model is a superset of the PKC model presented in Bhalla US and Iyengar R. Science (1999) 283(5400):381-7. The current version includes PKC turnover. This version includes the stimulating pools Ca, AA and DAG as well as the PKC activity within the synaptic signaling pathway since it is meant to be a self-contained pathway model rather than part of a network.
//genesis
// kkit Version 11 flat dumpfile
// Saved on Fri Aug 17 12:28:20 2007
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 7 7 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 0.030381 18228 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 0.028746 17247 0 0 0 6e+05 0 \
/kinetics/geometry cyan blue 2 7 0
simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0 0 0.0019877 1192.6 0 0 0 6e+05 0 \
/kinetics/geometry orange blue -2 7 0
simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0 0 0.01102 6611.9 0 0 0 6e+05 0 \
/kinetics/geometry pink blue -4 7 0
simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0 0 0.0032525 1951.5 0 0 0 \
6e+05 0 /kinetics/geometry yellow blue 4 7 0
simundump kpool /kinetics/PKC/PKC-basal* 0 0 0 0.016898 10139 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 0.0055271 3316.3 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 0.00032537 195.22 \
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 0.058588 35153 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 0.0028752 1725.1 \
1.5113e-13 0 0 6e+05 0 /kinetics/geometry white blue 2 1 0
simundump kpool /kinetics/PKC/PKC-cytosolic 0 0 1 0.84488 5.0693e+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 0.06743 40458 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 0.029966 17979 48000 0 0 6e+05 0 \
/kinetics/geometry red blue -4 -5 0
simundump kpool /kinetics/PKC/AA 0 0 5.5 5.4541 3.2725e+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 11.56 6.9362e+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 db26.g PKC_turnover pathway \
"Upinder S. Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "" "Genericl Mammalian" \
"Brain - Neuronal" "Cell membrane + Cytosol" \
"Quantitative match to experiments, Qualitative" In-house \
"Exact GENESIS implementation" "Approximates original data " 7 8 0
simundump xgraph /graphs/conc1 0 0 3992 0.00010007 0.067759 0
simundump xgraph /graphs/conc2 0 0 4000 0 0.29607 0
simundump xplot /graphs/conc1/PKC-active.Co 3 524288 \
"delete_plot.w ; edit_plot.D " yellow 0 0 1
simundump xgraph /moregraphs/conc3 0 0 4000 0 1 0
simundump xgraph /moregraphs/conc4 0 0 4000 0 1 0
simundump xcoredraw /edit/draw 0 -8 9 -10 15
simundump xtree /edit/draw/tree 0 \
/kinetics/#[],/kinetics/#[]/#[],/kinetics/#[]/#[]/#[][TYPE!=proto],/kinetics/#[]/#[]/#[][TYPE!=linkinfo]/##[] \
"edit_elm.D ; drag_from_edit.w " 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 \
"This model is a superset of the PKC model presented in Bhalla US and Iyengar R. Science (1999) 283(5400):381-7. The current version includes PKC turnover. This version includes the stimulating pools Ca, AA and DAG as well as the PKC activity within the synaptic signaling pathway since it is meant to be a self-contained pathway model rather than part of a network."
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