// DOQCS : http://doqcs.ncbs.res.in/
// Accession Name = cAMP_pathway
// Accession Number = 25
// Transcriber = Upinder S. Bhalla, NCBS
// Developer = Upinder S. Bhalla, NCBS
// Species = Generic mammalian
// Tissue = Brain - Neuronal
// Cell Compartment = Cell membrane + Cytosol
// Notes = This is a model of the canonical cAMP signaling pathway:
Ligand->Receptor->G-protein->Cyclase->cAMP->PKA.
It also includes phosphodiesterases to balance out cAMP formation.Bhalla US Methods Enzymol. 2002;345:3-23
//genesis
// kkit Version 11 flat dumpfile
// Saved on Fri Aug 17 12:20:31 2007
include kkit {argv 1}
FASTDT = 0.001
SIMDT = 0.001
CONTROLDT = 10
PLOTDT = 1
MAXTIME = 500
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 3 1 0
simundump group /kinetics/PKA 0 blue blue x 0 1 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 -16 -15 0
simundump kpool /kinetics/PKA/R2C2 0 0 0.5 0.5 3e+05 3e+05 0 0 6e+05 0 \
/kinetics/geometry white blue -21 -23 0
simundump kreac /kinetics/PKA/cAMP-bind-site-B1 0 9e-05 33 "" white blue -20 \
-25 0
simundump kreac /kinetics/PKA/cAMP-bind-site-B2 1 9e-05 33 "" white blue -18 \
-25 0
simundump kreac /kinetics/PKA/cAMP-bind-site-A1 1 0.000125 110 "" white blue \
-16 -25 0
simundump kreac /kinetics/PKA/cAMP-bind-site-A2 1 0.000125 32.5 "" white blue \
-14 -25 0
simundump kreac /kinetics/PKA/Release-C1 1 60 3e-05 "" white blue -14 -21 0
simundump kreac /kinetics/PKA/Release-C2 1 60 3e-05 "" white blue -14 -17 0
simundump kpool /kinetics/PKA/PKA-inhibitor 1 0 0.25 0.25 1.5e+05 1.5e+05 0 0 \
6e+05 0 /kinetics/geometry cyan blue -17 -19 0
simundump kreac /kinetics/PKA/inhib-PKA 1 1e-04 1 "" white blue -16 -21 0
simundump kpool /kinetics/PKA/inhibited-PKA 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry cyan blue -19 -19 0
simundump kpool /kinetics/PKA/cAMP.R2C2 0 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -19 -23 0
simundump kpool /kinetics/PKA/cAMP2.R2C2 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -17 -23 0
simundump kpool /kinetics/PKA/cAMP3.R2C2 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -15 -23 0
simundump kpool /kinetics/PKA/cAMP4.R2C2 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -13 -23 0
simundump kpool /kinetics/PKA/cAMP4.R2C 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -13 -19 0
simundump kpool /kinetics/PKA/cAMP4.R2 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry white blue -13 -15 0
simundump kpool /kinetics/cAMP 1 0 0 0 0 0 0 0 6e+05 2 /kinetics/geometry \
green black -13 -27 0
simundump kpool /kinetics/PKA-active 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry yellow black -15 -19 0
simundump kenz /kinetics/PKA-active/phosph-PDE 1 0 0 0 0 6e+05 1e-05 36 9 0 0 \
"" red yellow "" -6 -17 0
simundump group /kinetics/AC 1 blue blue x 0 1 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 -4 -15 0
simundump kpool /kinetics/AC/ATP 1 0 5000 5000 3e+09 3e+09 0 0 6e+05 4 \
/kinetics/geometry red blue -1 -19 0
simundump kpool /kinetics/AC/AMP 1 0 1000 1000 6e+08 6e+08 0 0 6e+05 4 \
/kinetics/geometry pink blue -5 -19 0
simundump kpool /kinetics/AC/cAMP-PDE 1 0 0.5 0.5 3e+05 3e+05 0 0 6e+05 0 \
/kinetics/geometry green blue -7 -19 0
simundump kenz /kinetics/AC/cAMP-PDE/PDE 1 0 0 0 0 6e+05 4.2e-06 40 10 0 0 "" \
red green "" -7 -21 0
simundump kpool /kinetics/AC/cAMP-PDE* 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry green blue -3 -19 0
simundump kenz /kinetics/AC/cAMP-PDE*/PDE* 1 0 0 0 0 6e+05 8.4e-06 80 20 0 0 \
"" red green "" -3 -21 0
simundump kreac /kinetics/AC/dephosph-PDE 1 0.1 0 "" white blue -4 -17 0
simundump kpool /kinetics/AC/Gs.AC 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry \
yellow blue -1 -23 0
simundump kenz /kinetics/AC/Gs.AC/cyclase 1 0 0 0 0 6e+05 7.5e-06 72 18 0 1 \
"" red yellow "" -1 -21 0
simundump kpool /kinetics/AC/AC 1 0 0.015 0.015 9000 9000 0 0 6e+05 0 \
/kinetics/geometry yellow blue 1 -23 0
simundump kreac /kinetics/AC/Gs-bind-AC 1 0.00083333 1 "" white blue 0 -21 0
simundump kpool /kinetics/GTP.Ga 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry \
red yellow 3 -5 0
simundump group /kinetics/Gs 1 blue black x 0 0 "" defaultfile \
/home2/bhalla/scripts/modules/defaultfile_0.g 0 0 0 -4 3 0
simundump kpool /kinetics/Gs/R 1 0 0.083333 0.083333 50000 50000 0 0 6e+05 0 \
/kinetics/geometry green blue -3 -1 0
simundump kpool /kinetics/Gs/L.R 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry \
green blue -1 -1 0
simundump kreac /kinetics/Gs/L-bind-R 1 1.6667e-07 0.1 "" white blue -2 -3 0
simundump kpool /kinetics/Gs/GDP.Gabc 1 0 1 1 6e+05 6e+05 0 0 6e+05 0 \
/kinetics/geometry yellow blue 1 -1 0
simundump kpool /kinetics/Gs/L.R.GDP.Gabc 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry orange blue -1 -5 0
simundump kpool /kinetics/Gs/L 1 0 0 0 0 0 0 0 6e+05 4 /kinetics/geometry \
green blue -3 -5 0
simundump kpool /kinetics/Gs/GDP.Ga 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry yellow blue 3 -1 0
simundump kpool /kinetics/Gs/Gbg 1 0 0 0 0 0 0 0 6e+05 0 /kinetics/geometry \
yellow blue 1 -5 0
simundump kreac /kinetics/Gs/Activate-Gs 1 0.025 0 "" white blue 0 -7 0
simundump kreac /kinetics/Gs/Trimerize-Gs 1 1e-05 0 "" white blue 2 -3 0
simundump kreac /kinetics/Gs/GTPase 1 0.066667 0 "" white blue 4 -3 0
simundump kpool /kinetics/Gs/R.GDP.Gabc 1 0 0 0 0 0 0 0 6e+05 0 \
/kinetics/geometry green blue -5 -1 0
simundump kreac /kinetics/Gs/L-bind-R.Gabc 1 8.3333e-06 0.1 "" white blue -4 \
-3 0
simundump kreac /kinetics/Gs/R-bind-Gabc 1 3.3333e-07 0.1 "" white blue -2 1 \
0
simundump kreac /kinetics/Gs/L.R-bind-Gabc 1 1.6667e-05 0.1 "" white blue 0 \
-3 0
simundump doqcsinfo /kinetics/doqcsinfo 0 db25.g cAMP_pathway network \
"Upinder S. Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "" "Generic Mammalian" \
"Brain - Neuronal" "Cell membrane + Cytosol" \
"Quantitative match to experiments, Qualitative" \
"Bhalla US Methods Enzymol. 2002;345:3-23 ( Peer-reviewed publication )" \
"Exact GENESIS implementation" "Approximates original data " 3 3 0
simundump xgraph /graphs/conc1 0 0 5400.1 0 0.034747 0
simundump xgraph /graphs/conc2 0 0 5400.1 0 0.019835 0
simundump xplot /graphs/conc1/L.Co 3 524288 \
"delete_plot.w ; edit_plot.D " green 0 0 1
simundump xplot /graphs/conc1/GTP.Ga.Co 3 524288 \
"delete_plot.w ; edit_plot.D " red 0 0 1
simundump xplot /graphs/conc1/cAMP.Co 3 524288 \
"delete_plot.w ; edit_plot.D " green 0 0 1
simundump xplot /graphs/conc1/PKA-active.Co 3 524288 \
"delete_plot.w ; edit_plot.D " yellow 0 0 1
simundump xplot /graphs/conc2/Gs.AC.Co 3 524288 \
"delete_plot.w ; edit_plot.D " yellow 0 0 1
simundump xgraph /moregraphs/conc3 0 0 5400.1 0 0.1 0
simundump xgraph /moregraphs/conc4 0 0 5400.1 0 0.1 0
simundump xcoredraw /edit/draw 0 -23 6 -29 5
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 \
""
addmsg /kinetics/PKA/cAMP-bind-site-B1 /kinetics/PKA/R2C2 REAC A B
addmsg /kinetics/PKA/R2C2 /kinetics/PKA/cAMP-bind-site-B1 SUBSTRATE n
addmsg /kinetics/PKA/cAMP.R2C2 /kinetics/PKA/cAMP-bind-site-B1 PRODUCT n
addmsg /kinetics/cAMP /kinetics/PKA/cAMP-bind-site-B1 SUBSTRATE n
addmsg /kinetics/PKA/cAMP.R2C2 /kinetics/PKA/cAMP-bind-site-B2 SUBSTRATE n
addmsg /kinetics/cAMP /kinetics/PKA/cAMP-bind-site-B2 SUBSTRATE n
addmsg /kinetics/PKA/cAMP2.R2C2 /kinetics/PKA/cAMP-bind-site-B2 PRODUCT n
addmsg /kinetics/PKA/cAMP2.R2C2 /kinetics/PKA/cAMP-bind-site-A1 SUBSTRATE n
addmsg /kinetics/cAMP /kinetics/PKA/cAMP-bind-site-A1 SUBSTRATE n
addmsg /kinetics/PKA/cAMP3.R2C2 /kinetics/PKA/cAMP-bind-site-A1 PRODUCT n
addmsg /kinetics/cAMP /kinetics/PKA/cAMP-bind-site-A2 SUBSTRATE n
addmsg /kinetics/PKA/cAMP3.R2C2 /kinetics/PKA/cAMP-bind-site-A2 SUBSTRATE n
addmsg /kinetics/PKA/cAMP4.R2C2 /kinetics/PKA/cAMP-bind-site-A2 PRODUCT n
addmsg /kinetics/PKA/cAMP4.R2C2 /kinetics/PKA/Release-C1 SUBSTRATE n
addmsg /kinetics/PKA-active /kinetics/PKA/Release-C1 PRODUCT n
addmsg /kinetics/PKA/cAMP4.R2C /kinetics/PKA/Release-C1 PRODUCT n
addmsg /kinetics/PKA/cAMP4.R2C /kinetics/PKA/Release-C2 SUBSTRATE n
addmsg /kinetics/PKA-active /kinetics/PKA/Release-C2 PRODUCT n
addmsg /kinetics/PKA/cAMP4.R2 /kinetics/PKA/Release-C2 PRODUCT n
addmsg /kinetics/PKA/inhib-PKA /kinetics/PKA/PKA-inhibitor REAC A B
addmsg /kinetics/PKA-active /kinetics/PKA/inhib-PKA SUBSTRATE n
addmsg /kinetics/PKA/PKA-inhibitor /kinetics/PKA/inhib-PKA SUBSTRATE n
addmsg /kinetics/PKA/inhibited-PKA /kinetics/PKA/inhib-PKA PRODUCT n
addmsg /kinetics/PKA/inhib-PKA /kinetics/PKA/inhibited-PKA REAC B A
addmsg /kinetics/PKA/cAMP-bind-site-B1 /kinetics/PKA/cAMP.R2C2 REAC B A
addmsg /kinetics/PKA/cAMP-bind-site-B2 /kinetics/PKA/cAMP.R2C2 REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-B2 /kinetics/PKA/cAMP2.R2C2 REAC B A
addmsg /kinetics/PKA/cAMP-bind-site-A1 /kinetics/PKA/cAMP2.R2C2 REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-A1 /kinetics/PKA/cAMP3.R2C2 REAC B A
addmsg /kinetics/PKA/cAMP-bind-site-A2 /kinetics/PKA/cAMP3.R2C2 REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-A2 /kinetics/PKA/cAMP4.R2C2 REAC B A
addmsg /kinetics/PKA/Release-C1 /kinetics/PKA/cAMP4.R2C2 REAC A B
addmsg /kinetics/PKA/Release-C1 /kinetics/PKA/cAMP4.R2C REAC B A
addmsg /kinetics/PKA/Release-C2 /kinetics/PKA/cAMP4.R2C REAC A B
addmsg /kinetics/PKA/Release-C2 /kinetics/PKA/cAMP4.R2 REAC B A
addmsg /kinetics/PKA/cAMP-bind-site-B1 /kinetics/cAMP REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-B2 /kinetics/cAMP REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-A1 /kinetics/cAMP REAC A B
addmsg /kinetics/PKA/cAMP-bind-site-A2 /kinetics/cAMP REAC A B
addmsg /kinetics/AC/Gs.AC/cyclase /kinetics/cAMP MM_PRD pA
addmsg /kinetics/AC/cAMP-PDE*/PDE* /kinetics/cAMP REAC sA B
addmsg /kinetics/AC/cAMP-PDE/PDE /kinetics/cAMP REAC sA B
addmsg /kinetics/PKA/Release-C1 /kinetics/PKA-active REAC B A
addmsg /kinetics/PKA/Release-C2 /kinetics/PKA-active REAC B A
addmsg /kinetics/PKA/inhib-PKA /kinetics/PKA-active REAC A B
addmsg /kinetics/PKA-active/phosph-PDE /kinetics/PKA-active REAC eA B
addmsg /kinetics/PKA-active /kinetics/PKA-active/phosph-PDE ENZYME n
addmsg /kinetics/AC/cAMP-PDE /kinetics/PKA-active/phosph-PDE SUBSTRATE n
addmsg /kinetics/AC/Gs.AC/cyclase /kinetics/AC/ATP REAC sA B
addmsg /kinetics/AC/cAMP-PDE*/PDE* /kinetics/AC/AMP MM_PRD pA
addmsg /kinetics/AC/cAMP-PDE/PDE /kinetics/AC/AMP MM_PRD pA
addmsg /kinetics/AC/cAMP-PDE/PDE /kinetics/AC/cAMP-PDE REAC eA B
addmsg /kinetics/AC/dephosph-PDE /kinetics/AC/cAMP-PDE REAC B A
addmsg /kinetics/PKA-active/phosph-PDE /kinetics/AC/cAMP-PDE REAC sA B
addmsg /kinetics/AC/cAMP-PDE /kinetics/AC/cAMP-PDE/PDE ENZYME n
addmsg /kinetics/cAMP /kinetics/AC/cAMP-PDE/PDE SUBSTRATE n
addmsg /kinetics/AC/cAMP-PDE*/PDE* /kinetics/AC/cAMP-PDE* REAC eA B
addmsg /kinetics/AC/dephosph-PDE /kinetics/AC/cAMP-PDE* REAC A B
addmsg /kinetics/PKA-active/phosph-PDE /kinetics/AC/cAMP-PDE* MM_PRD pA
addmsg /kinetics/AC/cAMP-PDE* /kinetics/AC/cAMP-PDE*/PDE* ENZYME n
addmsg /kinetics/cAMP /kinetics/AC/cAMP-PDE*/PDE* SUBSTRATE n
addmsg /kinetics/AC/cAMP-PDE* /kinetics/AC/dephosph-PDE SUBSTRATE n
addmsg /kinetics/AC/cAMP-PDE /kinetics/AC/dephosph-PDE PRODUCT n
addmsg /kinetics/AC/Gs-bind-AC /kinetics/AC/Gs.AC REAC B A
addmsg /kinetics/AC/Gs.AC /kinetics/AC/Gs.AC/cyclase ENZYME n
addmsg /kinetics/AC/ATP /kinetics/AC/Gs.AC/cyclase SUBSTRATE n
addmsg /kinetics/AC/Gs-bind-AC /kinetics/AC/AC REAC A B
addmsg /kinetics/AC/AC /kinetics/AC/Gs-bind-AC SUBSTRATE n
addmsg /kinetics/AC/Gs.AC /kinetics/AC/Gs-bind-AC PRODUCT n
addmsg /kinetics/GTP.Ga /kinetics/AC/Gs-bind-AC SUBSTRATE n
addmsg /kinetics/AC/Gs-bind-AC /kinetics/GTP.Ga REAC A B
addmsg /kinetics/Gs/GTPase /kinetics/GTP.Ga REAC A B
addmsg /kinetics/Gs/Activate-Gs /kinetics/GTP.Ga REAC B A
addmsg /kinetics/Gs/L-bind-R /kinetics/Gs/R REAC A B
addmsg /kinetics/Gs/R-bind-Gabc /kinetics/Gs/R REAC A B
addmsg /kinetics/Gs/L-bind-R /kinetics/Gs/L.R REAC B A
addmsg /kinetics/Gs/L.R-bind-Gabc /kinetics/Gs/L.R REAC A B
addmsg /kinetics/Gs/Activate-Gs /kinetics/Gs/L.R REAC B A
addmsg /kinetics/Gs/R /kinetics/Gs/L-bind-R SUBSTRATE n
addmsg /kinetics/Gs/L /kinetics/Gs/L-bind-R SUBSTRATE n
addmsg /kinetics/Gs/L.R /kinetics/Gs/L-bind-R PRODUCT n
addmsg /kinetics/Gs/Trimerize-Gs /kinetics/Gs/GDP.Gabc REAC B A
addmsg /kinetics/Gs/L.R-bind-Gabc /kinetics/Gs/GDP.Gabc REAC A B
addmsg /kinetics/Gs/R-bind-Gabc /kinetics/Gs/GDP.Gabc REAC A B
addmsg /kinetics/Gs/L.R-bind-Gabc /kinetics/Gs/L.R.GDP.Gabc REAC B A
addmsg /kinetics/Gs/L-bind-R.Gabc /kinetics/Gs/L.R.GDP.Gabc REAC B A
addmsg /kinetics/Gs/Activate-Gs /kinetics/Gs/L.R.GDP.Gabc REAC A B
addmsg /kinetics/Gs/L-bind-R /kinetics/Gs/L REAC A B
addmsg /kinetics/Gs/L-bind-R.Gabc /kinetics/Gs/L REAC A B
addmsg /kinetics/Gs/GTPase /kinetics/Gs/GDP.Ga REAC B A
addmsg /kinetics/Gs/Trimerize-Gs /kinetics/Gs/GDP.Ga REAC A B
addmsg /kinetics/Gs/Trimerize-Gs /kinetics/Gs/Gbg REAC A B
addmsg /kinetics/Gs/Activate-Gs /kinetics/Gs/Gbg REAC B A
addmsg /kinetics/Gs/L.R.GDP.Gabc /kinetics/Gs/Activate-Gs SUBSTRATE n
addmsg /kinetics/Gs/Gbg /kinetics/Gs/Activate-Gs PRODUCT n
addmsg /kinetics/Gs/L.R /kinetics/Gs/Activate-Gs PRODUCT n
addmsg /kinetics/GTP.Ga /kinetics/Gs/Activate-Gs PRODUCT n
addmsg /kinetics/Gs/GDP.Ga /kinetics/Gs/Trimerize-Gs SUBSTRATE n
addmsg /kinetics/Gs/Gbg /kinetics/Gs/Trimerize-Gs SUBSTRATE n
addmsg /kinetics/Gs/GDP.Gabc /kinetics/Gs/Trimerize-Gs PRODUCT n
addmsg /kinetics/GTP.Ga /kinetics/Gs/GTPase SUBSTRATE n
addmsg /kinetics/Gs/GDP.Ga /kinetics/Gs/GTPase PRODUCT n
addmsg /kinetics/Gs/L-bind-R.Gabc /kinetics/Gs/R.GDP.Gabc REAC A B
addmsg /kinetics/Gs/R-bind-Gabc /kinetics/Gs/R.GDP.Gabc REAC B A
addmsg /kinetics/Gs/L /kinetics/Gs/L-bind-R.Gabc SUBSTRATE n
addmsg /kinetics/Gs/L.R.GDP.Gabc /kinetics/Gs/L-bind-R.Gabc PRODUCT n
addmsg /kinetics/Gs/R.GDP.Gabc /kinetics/Gs/L-bind-R.Gabc SUBSTRATE n
addmsg /kinetics/Gs/GDP.Gabc /kinetics/Gs/R-bind-Gabc SUBSTRATE n
addmsg /kinetics/Gs/R /kinetics/Gs/R-bind-Gabc SUBSTRATE n
addmsg /kinetics/Gs/R.GDP.Gabc /kinetics/Gs/R-bind-Gabc PRODUCT n
addmsg /kinetics/Gs/GDP.Gabc /kinetics/Gs/L.R-bind-Gabc SUBSTRATE n
addmsg /kinetics/Gs/L.R /kinetics/Gs/L.R-bind-Gabc SUBSTRATE n
addmsg /kinetics/Gs/L.R.GDP.Gabc /kinetics/Gs/L.R-bind-Gabc PRODUCT n
addmsg /kinetics/Gs/L /graphs/conc1/L.Co PLOT Co *L.Co *green
addmsg /kinetics/GTP.Ga /graphs/conc1/GTP.Ga.Co PLOT Co *GTP.Ga.Co *red
addmsg /kinetics/cAMP /graphs/conc1/cAMP.Co PLOT Co *cAMP.Co *green
addmsg /kinetics/PKA-active /graphs/conc1/PKA-active.Co PLOT Co *PKA-active.Co *yellow
addmsg /kinetics/AC/Gs.AC /graphs/conc2/Gs.AC.Co PLOT Co *Gs.AC.Co *yellow
enddump
// End of dump
call /kinetics/PKA/notes LOAD \
"General ref: Taylor et al Ann Rev Biochem 1990 59:971-1005" \
""
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/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. Take mean" \
"which comes to 2e-13 #/cell" \
"Smith et al PNAS USA 78:3 1591-1595 1981 have better data." \
"First kf/kb=2.1e7/M = 3.5e-5 (#/cell)." \
"Ogreid and Doskeland Febs Lett 129:2 287-292 1981 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 B. This gives kf/kb = .7e-7M * 1e6 / (6e5^2) : 1/(6e5^2)" \
"= 2e-13:2.77e-12" \
"Smith et al have better values. They say that this is" \
"cooperative, so the consts are now kf/kb =8.3e-4"
call /kinetics/PKA/Release-C1/notes LOAD \
"This has to be fast, as the activation of PKA by cAMP" \
"is also fast." \
"kf was 10" \
""
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 \
"This has to be set to zero for matching the expts in vitro." \
"In vivo we need to consider the inhibition though." \
"" \
""
call /kinetics/PKA/cAMP.R2C2/notes LOAD \
"CoInit was .0624" \
""
call /kinetics/PKA/cAMP4.R2/notes LOAD \
"Starts at 0.15 for the test of fig 6 in Smith et al, but we aren't using" \
"that paper any more."
call /kinetics/cAMP/notes LOAD \
"Key second messenger."
call /kinetics/PKA-active/phosph-PDE/notes LOAD \
"See Bramson et al CRC crit rev Biochem 15:2 93-124." \
"The rates there are for peptide substrates and too fast." \
"Scaled down by a factor of 3 as per" \
"Cohen et al FEBS Lett 76:182-86 (1977)."
call /kinetics/AC/notes LOAD \
"Adenylyl cyclase, also known as adenylate cyclase." \
"There are some ten isoforms, but here I represent only" \
"the canonical Gs-stimulated activity."
call /kinetics/AC/ATP/notes LOAD \
"ATP is present in all cells between 2 and 10 mM. " \
"See Lehninger. It is assumed buffered since the" \
"metabolic activity will take care of its levels."
call /kinetics/AC/AMP/notes LOAD \
"Assumed buffered to 1 mM. Value is irrelevant" \
"to simulation."
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 at about 0.5 uM."
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" \
"Km ~2 uM, Vmax est ~ 10 umol/min/mg for pure form." \
"Brain protein is 93 kD but this was 67." \
"So k3 ~10, k2 ~40, k1 ~4.2e-6"
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."
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 etc is still unknown."
call /kinetics/AC/Gs.AC/notes LOAD \
"This is the active form of the cyclase." \
""
call /kinetics/AC/Gs.AC/cyclase/notes LOAD \
"See Feinstein et al PNAS 88:10173-10177," \
"Jacobowitz et al JBC 286(6):3829-3832" \
"Smigel, JBC 261(4):1976-1982 (1986)"
call /kinetics/AC/AC/notes LOAD \
"AC is present at rather low levels. Here we use" \
"0.015 uM which is meant to lump various isoforms." \
"None of the isoforms nor the other specific regulators" \
"are included here." \
"Jacobowitz, PhD thesis."
call /kinetics/AC/Gs-bind-AC/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 thesis (Mount Sinai 1995) data indicates" \
"it is more like 2 nM." \
""
call /kinetics/GTP.Ga/notes LOAD \
"Activated G protein. " \
"Supposed to be 15-40% of total Gs when max stim."
call /kinetics/Gs/notes LOAD \
"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 rec activation of Gq from Fay et al Biochem 30 5066-5075 1991"
call /kinetics/Gs/R/notes LOAD \
"A typical number of receptors per cell is about 50000."
call /kinetics/Gs/L.R/notes LOAD \
"Ligand.Receptor complex" \
""
call /kinetics/Gs/L-bind-R/notes LOAD \
"Ligand binding to receptor." \
"" \
"From Gether et al JBC 270:28268-28275 (1995) the binding" \
"to the purified receptor is at about 1 uM, but the" \
"conformational change only happens at 30 uM. We'll take" \
"1 uM for this, since it is already much weaker binding" \
"than to the R.Gs complex. The time-course from this" \
"paper appears remarkably slow, based on physiological data" \
"I estimate more like 10 sec." \
""
call /kinetics/Gs/GDP.Gabc/notes LOAD \
"The resting state of Gs: GDP bound to trimer." \
"" \
"From Pang and Sternweis JBC 265:30 18707-12 1990 we get " \
"conc est 1.6 uM to 0.8 uM. We'll use 1 uM." \
""
call /kinetics/Gs/L.R.GDP.Gabc/notes LOAD \
"This is the ternary complex, where all the action" \
"happens. There are actually a lot more steps here, " \
"including a final step where the GTP binds the" \
"L.R.Ga complex and causes the release of GTP.Ga from" \
"the L.R. For simplicity this is excluded."
call /kinetics/Gs/L/notes LOAD \
"This ligand could be any of several which bind" \
"to the beta adrenergic receptor and other G-protein" \
"coupled receptors which activate AC. For the" \
"sake of argument, call it isoproterenol."
call /kinetics/Gs/GDP.Ga/notes LOAD \
"The inactive GDP-bound form of Gs alpha."
call /kinetics/Gs/Gbg/notes LOAD \
"The Gbetagamma dimer."
call /kinetics/Gs/Activate-Gs/notes LOAD \
"This step combines several stages in GTP.Galpha release." \
"" \
"From Berstein et al activation is at .35 - 0.7/min" \
"From Fay et al Biochem 30 5066-5075 1991 kf = .01/sec." \
"From Brandt and Ross JBC 261(4):1656-1664 (1986)" \
"and Ransan et al Biochem J 283(2):519-524 (1992) rates" \
"around 2.5/min to 1.5/min are better."
call /kinetics/Gs/Trimerize-Gs/notes LOAD \
"Negligible back-reaction." \
""
call /kinetics/Gs/GTPase/notes LOAD \
"From Brandt and Ross JBC 261(4):1656-1664," \
"rate is 4/min and is agonist independent." \
"I treat this as irreversible."
call /kinetics/Gs/R.GDP.Gabc/notes LOAD \
"Fraction of R.GDP.Gabc is about 50% of total R," \
"from Fay et al. Biochemistry 30:5066-5075(1991)" \
"Since this is not the same receptor, this value is a bit" \
"uncertain." \
""
call /kinetics/Gs/L-bind-R.Gabc/notes LOAD \
"From Seifert et al Mol. Pharmacol 56:348-358 (1999)" \
"The EC50 for ISO is about 20 nM."
call /kinetics/Gs/R-bind-Gabc/notes LOAD \
"Receptor binding to Gs. Scale it to the same" \
"slow rates described by Fay et al for L.R to L.R.G." \
"From detailed balance, Kd is 50."
call /kinetics/Gs/L.R-bind-Gabc/notes LOAD \
"See Fay et al Biochem 30 5066-5075 1991." \
"kf is 0.01/sec but does not account for Gs levels." \
"kb is 0.0001/sec. The fraction of RG is about 50%, so" \
"we can estimate Kd at about the same as for Gs basal levels." \
"" \
"This rate has to be faster since it has to feed GTP.Ga" \
"into the system faster than the GTPase." \
"Waldhoer et al Mol Pharmacol 53:808-818 1988" \
"say affinity for A1adenosine/Gi is 10 nM."
call /kinetics/doqcsinfo/notes LOAD \
"This is a model of the canonical cAMP signaling pathway:
Ligand->Receptor->G-protein->Cyclase->cAMP->PKA.
It also includes phosphodiesterases to balance out cAMP formation.Bhalla US Methods Enzymol. 2002;345:3-23"
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