// DOQCS :http://doqcs.ncbs.res.in/ // Accession Name = MAPK_network_2003 // Accession Number = 50 // Pathway Name = PP1 // Pathway Number = 218 // Transcriber = Upinder S. Bhalla, NCBS // Developer = Upinder S. Bhalla, NCBS // Species = Generic mammalian // Tissue = Brain - Neuronal // Cell Compartment = Synapse // Notes = This is a network model of many pathways present at the neuronal synapse. The network has properties of temporal tuning as well as steady-state computational properties. In its default form the network is bistable.Bhalla US Biophys J. 2004 Aug;87(2):745-53 //genesis // kkit Version 11 flat dumpfile // Saved on Tue Dec 13 12:24:44 2005 include kkit {argv 1} FASTDT = 1e-05 SIMDT = 0.001 CONTROLDT = 1 PLOTDT = 0.1 MAXTIME = 600 TRANSIENT_TIME = 30 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 1.6667e-21 3 sphere "" white black \ 110 21 0 simundump group /kinetics/sGC 0 yellow black x 0 1 "" sGC \ /home2/bhalla/scripts/modules/sGC_0.g 0 0 0 106 19 0 simundump kpool /kinetics/sGC/cGMP 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry \ blue yellow 82 18 0 simundump kpool /kinetics/sGC/GTP 0 0 1000 1000 1000 1000 0 0 1 4 \ /kinetics/geometry 58 yellow 103 19 0 simundump kpool /kinetics/sGC/sGC 0 0 3 3 3 3 0 0 1 0 /kinetics/geometry 27 \ yellow 112 13 0 simundump kreac /kinetics/sGC/CObindsGCa 0 0.12 28 "" white yellow 105 10 0 simundump kpool /kinetics/sGC/Heme 0 0 11.3 11.3 11.3 11.3 0 0 1 0 \ /kinetics/geometry 53 yellow 113 4 0 simundump kpool /kinetics/sGC/CO 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry 62 \ yellow 116 9 0 simundump kpool /kinetics/sGC/Hemeoxyg2 0 0 2 2 2 2 0 0 1 0 \ /kinetics/geometry 20 yellow 97 6 0 simundump kenz /kinetics/sGC/Hemeoxyg2/HOXY 0 0 0 0 0 1 0.46789 1.4224 0.3556 \ 0 0 "" red 20 "" 104 6 0 simundump kpool /kinetics/sGC/GC6-CO 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry 0 \ yellow 100 14 0 simundump kreac /kinetics/sGC/K 0 0.95 0 "" white yellow 95 10 0 simundump kreac /kinetics/sGC/k 0 1000 0 "" white yellow 81 10 0 simundump kpool /kinetics/sGC/GC5_CO 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry 8 \ yellow 90 13 0 simundump kenz /kinetics/sGC/GC5_CO/activeGC 0 0 0 0 0 1 545.4 218.16 54.54 0 \ 1 "" red 8 "" 89 15 0 simundump kpool /kinetics/sGC/dissoCO 0 0 0.1142 0.1142 0.1142 0.1142 0 0 1 4 \ /kinetics/geometry 22 yellow 88 8 0 simundump kpool /kinetics/sGC/PDE 0 0 5 5 5 5 0 0 1 0 /kinetics/geometry 51 \ yellow 75 14 0 simundump kenz /kinetics/sGC/PDE/kenz 0 0 0 0 0 1 9.675 15.48 3.87 0 0 "" red \ 51 "" 75 15 0 simundump kpool /kinetics/sGC/5prime_GMP 0 0 0 0 0 0 0 0 1 0 \ /kinetics/geometry 34 yellow 71 18 0 simundump kpool /kinetics/sGC/Ery_HbO2 0 0 5 5 5 5 0 0 1 0 /kinetics/geometry \ 62 yellow 76 8 0 simundump kpool /kinetics/sGC/COHb 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry 0 \ yellow 73 4 0 simundump kreac /kinetics/sGC/CObindsHbO2 0 0.17 0.0078 "" white yellow 85 5 \ 0 simundump doqcsinfo /kinetics/doqcsinfo 0 pdb218.g PP1 pathway \ "Upinder S. Bhalla, NCBS" "Upinder S. Bhalla, NCBS" "citation here" \ "Generic Mammalian" "Brain - Neuronal" Synapse Qualitative \ "Bhalla US Biophys J. 2004 Aug;87(2):745-53 ( peer-reviewed publication )" \ "Exact GENESIS implementation" "Approximates original data " 101 21 0 simundump xgraph /graphs/conc1 0 0 600 0 0.00034388 0 simundump xgraph /graphs/conc2 0 0 600 0 9.0568 0 simundump xplot /graphs/conc1/cGMP.Co 3 524288 \ "delete_plot.w ; edit_plot.D " blue 0 0 1 simundump xplot /graphs/conc2/CO.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 62 0 0 1 simundump xgraph /moregraphs/conc3 0 0 600 0 6.1089e-05 0 simundump xgraph /moregraphs/conc4 0 0 600 0 0.064304 0 simundump xplot /moregraphs/conc3/GC5_CO.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 8 0 0 1 simundump xplot /moregraphs/conc4/GC6-CO.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 0 0 0 1 simundump xcoredraw /edit/draw 0 69 118 2 23 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 \ "Carbon Monoxide is an activator of soluble Gunalyl Cyclase and has been implicated as " \ "a neuronal messenger.(Ingi et al., 1996, Neuron, 16:835-842). CO binds to the heme group" \ "on sGC, similar to NO binding. Exogenous CO at similar conc. to endogenous levels blocked" \ "the NO-mediated cGMP release.(Ingi et al., 1996)" \ "Olfactory receptor neurons have been used by Ingi et al., to investigate the relationship" \ "of CO to cGMP levels, as these cells have high levels of HO activity but no NOS activity." \ "Kharitonov et al., PNAS, 1995, 92:2568-2571, report the presence of a six and five co-ordinate" \ "intermediate of carboxy GC, induced by CO. They ofcourse used purified GC from bovine lung. But " \ "considering CO activity is almost similar in different tissues, one or two rates have been used" \ "from their reported data." addmsg /kinetics/sGC/GC5_CO/activeGC /kinetics/sGC/cGMP MM_PRD pA addmsg /kinetics/sGC/PDE/kenz /kinetics/sGC/cGMP REAC sA B addmsg /kinetics/sGC/GC5_CO/activeGC /kinetics/sGC/GTP REAC sA B addmsg /kinetics/sGC/CObindsGCa /kinetics/sGC/sGC REAC A B addmsg /kinetics/sGC/sGC /kinetics/sGC/CObindsGCa SUBSTRATE n addmsg /kinetics/sGC/CO /kinetics/sGC/CObindsGCa SUBSTRATE n addmsg /kinetics/sGC/GC6-CO /kinetics/sGC/CObindsGCa PRODUCT n addmsg /kinetics/sGC/Hemeoxyg2/HOXY /kinetics/sGC/Heme REAC sA B addmsg /kinetics/sGC/Hemeoxyg2/HOXY /kinetics/sGC/CO MM_PRD pA addmsg /kinetics/sGC/CObindsGCa /kinetics/sGC/CO REAC A B addmsg /kinetics/sGC/Hemeoxyg2/HOXY /kinetics/sGC/Hemeoxyg2 REAC eA B addmsg /kinetics/sGC/Hemeoxyg2 /kinetics/sGC/Hemeoxyg2/HOXY ENZYME n addmsg /kinetics/sGC/Heme /kinetics/sGC/Hemeoxyg2/HOXY SUBSTRATE n addmsg /kinetics/sGC/CObindsGCa /kinetics/sGC/GC6-CO REAC B A addmsg /kinetics/sGC/K /kinetics/sGC/GC6-CO REAC A B addmsg /kinetics/sGC/GC6-CO /kinetics/sGC/K SUBSTRATE n addmsg /kinetics/sGC/GC5_CO /kinetics/sGC/K PRODUCT n addmsg /kinetics/sGC/GC5_CO /kinetics/sGC/k SUBSTRATE n addmsg /kinetics/sGC/dissoCO /kinetics/sGC/k PRODUCT n addmsg /kinetics/sGC/K /kinetics/sGC/GC5_CO REAC B A addmsg /kinetics/sGC/k /kinetics/sGC/GC5_CO REAC A B addmsg /kinetics/sGC/GC5_CO /kinetics/sGC/GC5_CO/activeGC ENZYME n addmsg /kinetics/sGC/GTP /kinetics/sGC/GC5_CO/activeGC SUBSTRATE n addmsg /kinetics/sGC/k /kinetics/sGC/dissoCO REAC B A addmsg /kinetics/sGC/CObindsHbO2 /kinetics/sGC/dissoCO REAC A B addmsg /kinetics/sGC/PDE/kenz /kinetics/sGC/PDE REAC eA B addmsg /kinetics/sGC/PDE /kinetics/sGC/PDE/kenz ENZYME n addmsg /kinetics/sGC/cGMP /kinetics/sGC/PDE/kenz SUBSTRATE n addmsg /kinetics/sGC/PDE/kenz /kinetics/sGC/5prime_GMP MM_PRD pA addmsg /kinetics/sGC/CObindsHbO2 /kinetics/sGC/Ery_HbO2 REAC A B addmsg /kinetics/sGC/CObindsHbO2 /kinetics/sGC/COHb REAC B A addmsg /kinetics/sGC/dissoCO /kinetics/sGC/CObindsHbO2 SUBSTRATE n addmsg /kinetics/sGC/Ery_HbO2 /kinetics/sGC/CObindsHbO2 SUBSTRATE n addmsg /kinetics/sGC/COHb /kinetics/sGC/CObindsHbO2 PRODUCT n addmsg /kinetics/sGC/cGMP /graphs/conc1/cGMP.Co PLOT Co *cGMP.Co *blue addmsg /kinetics/sGC/CO /graphs/conc2/CO.Co PLOT Co *CO.Co *62 addmsg /kinetics/sGC/GC5_CO /moregraphs/conc3/GC5_CO.Co PLOT Co *GC5_CO.Co *8 addmsg /kinetics/sGC/GC6-CO /moregraphs/conc4/GC6-CO.Co PLOT Co *GC6-CO.Co *0 enddump // End of dump call /kinetics/sGC/notes LOAD \ "This model features the basis of CO activating sGC. Kharitonov et al.," \ "1995, PNAS, 92:2568-2571, report the presence of a six coordinate" \ "and an active five coord carboxy species, in the activation " \ "mechanism, though the five coord sp. is present in small amounts." \ "" call /kinetics/sGC/GTP/notes LOAD \ "Under in vivo conditions, GTP is present in excess, ~ 1mM." call /kinetics/sGC/sGC/notes LOAD \ "sGC is enriched in purkine cells ~3 uM (Conc from Shinya Kuroda, assumed on " \ "the basis of reported data in Ariano et al., 1982, PNAS,79: 297-300)" \ "soluble Guanylyl Cyclase localization is virtually identical to that of" \ "HO-2 in numerous brain regions.(Ingi et al., 1995, J Neurosci., 15:8214-8222)," \ "in contrast to discrepancies in the localization of NOS and sGC in the brain." call /kinetics/sGC/CObindsGCa/notes LOAD \ "This gives rise to the six co-ordinate carboxy GC." \ "Kharitonov et al., 1995, PNAS, 92:2568-2571 report CO association and" \ "dissociation rates at 1.2e5 /M/sec and 28 /sec respectively." \ "Kharitonov et al., 1999, Biochemistry, 38(33):10699-10706 report" \ "Ka at 7.86 +- 0.50 /mM." call /kinetics/sGC/Heme/notes LOAD \ "Total cellular heme determined spectrophotometrically to be 1.5 nmol/mg protein." \ "(Ingi et al., 1996, Neuron,16:835-842), a value resembling reported heme content" \ "in neuronal tissues. " \ "Ingi et al., also reports in J Neurosci. 1996,16(18):5621-5628, that Brain" \ "has significant levels of heme (1.3 nmol/mg protein)" \ "Conc calculated/used 21.3" call /kinetics/sGC/CO/notes LOAD \ "CO is an endogenous modulator of sGC. It is produced by the" \ "oxidative cleavage by HO to yield CO and Biliverdin. It also" \ "binds to the heme group on sGC as NO and it may be competetive" \ "to NO with regard to the binding to the heme prosthetic group." \ "Like NO, it binds to the Iron in the heme, and activate Guanylyl Cyclase." \ "(Brune et al., 1987, Mol. Pharmacol.32, 497-504), Kharitonov" \ "et al., 1995, PNAS, 92:2568-2571)" \ "Because of the gaseous nature of CO, and its high affinity for hemoprotein," \ "its very difficult to determine the exact intracellular concentration of CO." \ "Endogenous CO level was calculated to be 50-160 pmol/mg protein or" \ "10-30 uM, by Ingi et al., J Neursoci 1996, 16(18): 5621-5628, on the assumption" \ "that the amount of CO produced for 10-30 mins is an effective concentration in the" \ "cell, taking into account the diffusion of CO. " \ "Using exogenous CO at the endogenous levels of 10-30 uM, significant " \ "elevation of GC activity is observed, though CO does not seem to be a " \ "rapid stimulator, but works as a modulator, producing slower and " \ "long-term effects (Ingi et al., 1996, J Neurosci.,16(18):5621-5628)." \ "" call /kinetics/sGC/Hemeoxyg2/notes LOAD \ "Heme oxygenase 2 (HO-2)-Highly expressed in Brain (Sun et al.," \ "1990, J Biol. Chem., 265: 8212-8217), with discrete neuronal localization" \ "demonstrated throughout the brain with in situ hybridisation and " \ "immunohistochemical studies (Verma et al., 1993, Science, 259:" \ "381-384). Mol. Wt. of HO-2 is 36 kDa.(Migita et al., JBC,1998,273(2):945-949.)" \ "Three mammalian isoforms have been identified. HO-1, is inducible " \ "and highly concentrated in tissues and involved in catabolism of heme proteins." \ "HO-3, is an isoform with low catalytic activity, with uncertain physiological role." \ "(Montellano, PRO., 2000, Curr Opin in Chem Biol, 4:221-227)" call /kinetics/sGC/Hemeoxyg2/HOXY/notes LOAD \ "Ingi et al., J Neurosci., 1996, 16(18):5621-5628, report the production" \ "rates of heme precursors and metabolites. The rate reported for CO from heme" \ "is 2.9 pmol/mg protein over 6 hr. Their results indicate high HO activity in brain" \ "(along with significant levels of heme) at around 280pmol of bilirubin/mg/min." \ "Montellano PRO, Curr. Opin. in Chem. Biol, 2000,4:221-227 and refs cited in his paper" \ "were also studied initially." \ "Km for free heme is around 3.8 +/- 0.5 uM.(Bonkovsky et al.," \ "1990, 189(1):155-166)" call /kinetics/sGC/GC6-CO/notes LOAD \ "The six-coordinate form of sGC bound to CO. This mechanism has been " \ "proved with results by Kharitonov et al., PNAS, 1995, 92:2568-2571." \ "Most of the Carboxy derivative of GC is six-coordinate." call /kinetics/sGC/K/notes LOAD \ "The transition from six co-ordinate to the five co-ordinate" \ "carboxy GC." \ "CO dissociation rate for 6 coord sp for heme is 0.95 /sec." \ "(Kharitonov et al., 1995, PNAS, 92:2568-2571)" call /kinetics/sGC/k/notes LOAD \ "The dissociation of CO from the active five co-ordinate GC. " \ "rate from Kharitonov et al., PNAS, 1995, 92:2568-2571." \ "Further justification include the fact that Soret absorption" \ "spectrum of GC-NO suggesting almost complete sonversion to five" \ "co-ordinate species. So, assuming that the five co-ord species" \ "is more active than the basal form, irrespective of the Ligand," \ "the percentage of five co-ordinate intermediate induced by CO " \ "was calculated to be 3% to 1.5%.(Kharitonov et al., 1995, PNAS)" \ "using mean value, ~ 2 +- 1 %, and kobs = 28/sec, k = 1*10^3/sec." \ "(Kharitonov et al., PNAS, 1995, 92:2568-2571)" call /kinetics/sGC/GC5_CO/notes LOAD \ "The active five coordinate Carboxy GC. Kharitonov et al., PNAS, 1995, 92:2568-2571 " \ "report the presence of a five coord carboxy species during the activation of GC by CO," \ "similar to the presence of a five coord species in the nitroxyl GC, during NO activation" \ "of sGC." call /kinetics/sGC/GC5_CO/activeGC/notes LOAD \ "Friebe et al., 1996, EMBO Journal, 15(24): 6863-6868 and back" \ "refs cited in their paper. " \ "They have studied the potentiation by YC-1 of CO activated sGC." \ "In the absence of YC-1, they report 3 fold stimulation of GC by" \ "CO, with 218 +- 11 nmol/min/mg of cGMP." \ "Vmax / Km increased by 100 X." call /kinetics/sGC/dissoCO/notes LOAD \ "The erythrocyte-associated hemoglobin has a critical role" \ "of being the primary CO-scavenging system. Locally generated" \ "CO is eliminated by hemoglobin in circulating erythrocytes and" \ "is gradually released into the alveolar space of the lung, where" \ "molecular oxygen is alternately bound to the heme. Most of the CO" \ "(Carbon Monoxide) generated in the body is exhaled into the " \ "airway." \ "(Suematsu M, Gasteroenterology 2001;120:1227-1240 and" \ "personal correspondence)" call /kinetics/sGC/PDE/notes LOAD \ "Phosphodiesterase : Degrades cGMP to 5prime_GMP" \ "Conc from Kotera et al., Eur J Biochem., 1997; 249:434-442" \ "and Kuroda et al., J Neurosci, 2001, 21(15):5693-5702" call /kinetics/sGC/PDE/kenz/notes LOAD \ "Km / Vmax -- 2 uM / 3.87 sec^-1." \ "rates from Turko et al., 1998, Biochem J, 329:505-510" \ "and Kuroda et al., J Neurosci, 2001, 21(15):5693-5702" call /kinetics/sGC/Ery_HbO2/notes LOAD \ "Erythrocyte associated hemoglobin -- This supposedly is the " \ "primary CO-scavenging system. " \ "(Suematsu M, personal correspondence)" call /kinetics/sGC/COHb/notes LOAD \ "Carboxy Hemoglobin, from which CO subsequently is released " \ "into the alveolar space of the lung, where molecular oxygen " \ "is alternately bound to the heme. Most of the CO generated " \ "in the body is thus exhaled into the airway." \ "(Suematsu M, personal correspondence)" call /kinetics/sGC/CObindsHbO2/notes LOAD \ "CO binds to hemoglobin, predominantly the erythrocyte associated" \ "hemoglobin. The affinity of hemoglobin for CO is 200-250 times" \ "that of oxygen, while relative affinities of heme proteins" \ "(myoglobin), cytochrome oxidase and cytochrome P-450 for CO" \ "are much lower. " \ "CO binds reversibly to hemoglobin to form Carboxy hemoglobin," \ "(COHb) from which CO is exhaled through the lungs. Primary " \ "source for rates, Migita et al., JBC, 1998, 273(2): 945-949," \ "and refs cited in their paper." call /kinetics/doqcsinfo/notes LOAD \ " This is a network model of many pathways present at the neuronal synapse. The network has properties of temporal tuning as well as steady-state computational properties. In its default form the network is bistable.Bhalla US Biophys J. 2004 Aug;87(2):745-53" complete_loading