// 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 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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 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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 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/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" complete_loading