// DOQCS :http://doqcs.ncbs.res.in/ // Accession Name = MAPK_network_2003 // Accession Number = 50 // Pathway Name = CaM // Pathway Number = 217 // 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 12:13:15 2005 include kkit {argv 1} FASTDT = 5e-05 SIMDT = 0.005 CONTROLDT = 10 PLOTDT = 5 MAXTIME = 6000 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 1.6667e-21 3 sphere "" white black 11 \ 11 0 simundump group /kinetics/MAPK 0 yellow black x 0 0 "" MAPK \ /home2/bhalla/scripts/modules/MAPK_0.g 0 0 0 1 10 0 simundump kpool /kinetics/MAPK/MAPK 0 0 0.3 0.3 0.3 0.3 0 0 1 0 \ /kinetics/geometry 35 yellow -8 -7 0 simundump kpool /kinetics/MAPK/MKKK 0 0 0.1 0.1 0.1 0.1 0 0 1 0 \ /kinetics/geometry 16 yellow -8 5 0 simundump kpool /kinetics/MAPK/MKK 0 0 0.3 0.3 0.3 0.3 0 0 1 0 \ /kinetics/geometry 60 yellow -8 -1 0 simundump kpool /kinetics/MAPK/int1 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry 30 yellow -4 4 0 simundump kenz /kinetics/MAPK/int1/2 0 0 0 0 0 0.001 156.25 1 0.25 0 1 "" red \ 30 "" -4 5 0 simundump kpool /kinetics/MAPK/MKKK-P 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry \ 51 yellow 0 5 0 simundump kenz /kinetics/MAPK/MKKK-P/3 0 0 0 0 0 0.001 8.3333 0.1 0.025 0 1 \ "" red 51 "" -4 2 0 simundump kenz /kinetics/MAPK/MKKK-P/4 0 0 0 0 0 0.001 8.3333 0.1 0.025 0 1 \ "" red 51 "" 4 2 0 simundump kpool /kinetics/MAPK/int3 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry blue yellow -4 -2 0 simundump kenz /kinetics/MAPK/int3/6 0 0 0 0 0 0.001 250 3 0.75 0 1 "" red \ blue "" -4 -1 0 simundump kpool /kinetics/MAPK/int5 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry 1 yellow -4 -8 0 simundump kenz /kinetics/MAPK/int5/10 0 0 0 0 0 0.001 166.67 2 0.5 0 1 "" red \ 1 "" -4 -7 0 simundump kpool /kinetics/MAPK/MKK-P 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry 5 \ yellow 0 -1 0 simundump kpool /kinetics/MAPK/MAPK-P 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry \ 55 yellow 0 -7 0 simundump kpool /kinetics/MAPK/int2 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry 2 yellow 4 -2 0 simundump kenz /kinetics/MAPK/int2/5 0 0 0 0 0 0.001 250 3 0.75 0 1 "" red 2 \ "" 4 -1 0 simundump kpool /kinetics/MAPK/int4 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry 17 yellow 4 -8 0 simundump kenz /kinetics/MAPK/int4/9 0 0 0 0 0 0.001 166.67 2 0.5 0 1 "" red \ 17 "" 4 -7 0 simundump kpool /kinetics/MAPK/Ras-MKKKK 0 0 0.001 0.001 0.001 0.001 0 0 1 0 \ /kinetics/geometry 47 yellow 6 8 0 simundump kenz /kinetics/MAPK/Ras-MKKKK/1 0 0 0 0 0 0.001 1250 10 2.5 0 1 "" \ red 47 "" -4 8 0 simundump kpool /kinetics/MAPK/inactiveRas-MKKK 0 0 0 0 0 0 0 0 1 0 \ /kinetics/geometry 30 yellow 11 8 0 simundump kreac /kinetics/MAPK/Neg_feedback 0 1 0.009 "" white yellow 11 2 0 simundump kpool /kinetics/MAPK/MKK-PP 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry \ 60 yellow 8 -1 0 simundump kenz /kinetics/MAPK/MKK-PP/7 0 0 0 0 0 0.001 8.3333 0.1 0.025 0 1 \ "" red 60 "" -4 -4 0 simundump kenz /kinetics/MAPK/MKK-PP/8 0 0 0 0 0 0.001 8.3333 0.1 0.025 0 1 \ "" red 60 "" 4 -4 0 simundump kpool /kinetics/MAPK/MAPK-PP 0 0 0 0 0 0 0 0 1 0 /kinetics/geometry \ 46 yellow 8 -7 0 simundump doqcsinfo /kinetics/doqcsinfo 0 pdb217.g CaM 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 " 8 11 0 simundump xgraph /graphs/conc1 0 0 6000 0 0.3 0 simundump xgraph /graphs/conc2 0 0 6000 4.5157e-05 0.3 0 simundump xplot /graphs/conc1/MAPK-PP.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 46 0 0 1 simundump xplot /graphs/conc1/MAPK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 35 0 0 1 simundump xplot /graphs/conc2/Ras-MKKKK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 47 0 0 1 simundump xplot /graphs/conc2/MAPK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 35 0 0 1 simundump xplot /graphs/conc2/MKKK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 16 0 0 1 simundump xplot /graphs/conc2/MKK.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 60 0 0 1 simundump xgraph /moregraphs/conc3 0 0 6000 0 1 0 simundump xgraph /moregraphs/conc4 0 0 6000 0 1 0 simundump xcoredraw /edit/draw 0 -10 13 -10 12 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 \ "22 Jan 2002" \ " " \ " This model is based on Kholodenko, B.N." \ " Eur. J. Biochem. 267, 1583-1588(2000)" \ "" addmsg /kinetics/MAPK/MKK-PP/7 /kinetics/MAPK/MAPK REAC sA B addmsg /kinetics/MAPK/int5/10 /kinetics/MAPK/MAPK MM_PRD pA addmsg /kinetics/MAPK/Ras-MKKKK/1 /kinetics/MAPK/MKKK REAC sA B addmsg /kinetics/MAPK/int1/2 /kinetics/MAPK/MKKK MM_PRD pA addmsg /kinetics/MAPK/MKKK-P/3 /kinetics/MAPK/MKK REAC sA B addmsg /kinetics/MAPK/int3/6 /kinetics/MAPK/MKK MM_PRD pA addmsg /kinetics/MAPK/int1 /kinetics/MAPK/int1/2 ENZYME n addmsg /kinetics/MAPK/MKKK-P /kinetics/MAPK/int1/2 SUBSTRATE n addmsg /kinetics/MAPK/Ras-MKKKK/1 /kinetics/MAPK/MKKK-P MM_PRD pA addmsg /kinetics/MAPK/int1/2 /kinetics/MAPK/MKKK-P REAC sA B addmsg /kinetics/MAPK/MKKK-P /kinetics/MAPK/MKKK-P/3 ENZYME n addmsg /kinetics/MAPK/MKK /kinetics/MAPK/MKKK-P/3 SUBSTRATE n addmsg /kinetics/MAPK/MKKK-P /kinetics/MAPK/MKKK-P/4 ENZYME n addmsg /kinetics/MAPK/MKK-P /kinetics/MAPK/MKKK-P/4 SUBSTRATE n addmsg /kinetics/MAPK/int3 /kinetics/MAPK/int3/6 ENZYME n addmsg /kinetics/MAPK/MKK-P /kinetics/MAPK/int3/6 SUBSTRATE n addmsg /kinetics/MAPK/int5 /kinetics/MAPK/int5/10 ENZYME n addmsg /kinetics/MAPK/MAPK-P /kinetics/MAPK/int5/10 SUBSTRATE n addmsg /kinetics/MAPK/MKKK-P/4 /kinetics/MAPK/MKK-P REAC sA B addmsg /kinetics/MAPK/MKKK-P/3 /kinetics/MAPK/MKK-P MM_PRD pA addmsg /kinetics/MAPK/int3/6 /kinetics/MAPK/MKK-P REAC sA B addmsg /kinetics/MAPK/int2/5 /kinetics/MAPK/MKK-P MM_PRD pA addmsg /kinetics/MAPK/MKK-PP/8 /kinetics/MAPK/MAPK-P REAC sA B addmsg /kinetics/MAPK/MKK-PP/7 /kinetics/MAPK/MAPK-P MM_PRD pA addmsg /kinetics/MAPK/int5/10 /kinetics/MAPK/MAPK-P REAC sA B addmsg /kinetics/MAPK/int4/9 /kinetics/MAPK/MAPK-P MM_PRD pA addmsg /kinetics/MAPK/int2 /kinetics/MAPK/int2/5 ENZYME n addmsg /kinetics/MAPK/MKK-PP /kinetics/MAPK/int2/5 SUBSTRATE n addmsg /kinetics/MAPK/int4 /kinetics/MAPK/int4/9 ENZYME n addmsg /kinetics/MAPK/MAPK-PP /kinetics/MAPK/int4/9 SUBSTRATE n addmsg /kinetics/MAPK/Neg_feedback /kinetics/MAPK/Ras-MKKKK REAC A B addmsg /kinetics/MAPK/Ras-MKKKK /kinetics/MAPK/Ras-MKKKK/1 ENZYME n addmsg /kinetics/MAPK/MKKK /kinetics/MAPK/Ras-MKKKK/1 SUBSTRATE n addmsg /kinetics/MAPK/Neg_feedback /kinetics/MAPK/inactiveRas-MKKK REAC B A addmsg /kinetics/MAPK/MAPK-PP /kinetics/MAPK/Neg_feedback SUBSTRATE n addmsg /kinetics/MAPK/Ras-MKKKK /kinetics/MAPK/Neg_feedback SUBSTRATE n addmsg /kinetics/MAPK/inactiveRas-MKKK /kinetics/MAPK/Neg_feedback PRODUCT n addmsg /kinetics/MAPK/MKKK-P/4 /kinetics/MAPK/MKK-PP MM_PRD pA addmsg /kinetics/MAPK/int2/5 /kinetics/MAPK/MKK-PP REAC sA B addmsg /kinetics/MAPK/MKK-PP /kinetics/MAPK/MKK-PP/7 ENZYME n addmsg /kinetics/MAPK/MAPK /kinetics/MAPK/MKK-PP/7 SUBSTRATE n addmsg /kinetics/MAPK/MKK-PP /kinetics/MAPK/MKK-PP/8 ENZYME n addmsg /kinetics/MAPK/MAPK-P /kinetics/MAPK/MKK-PP/8 SUBSTRATE n addmsg /kinetics/MAPK/MKK-PP/8 /kinetics/MAPK/MAPK-PP MM_PRD pA addmsg /kinetics/MAPK/int4/9 /kinetics/MAPK/MAPK-PP REAC sA B addmsg /kinetics/MAPK/Neg_feedback /kinetics/MAPK/MAPK-PP REAC A B addmsg /kinetics/MAPK/MAPK-PP /graphs/conc1/MAPK-PP.Co PLOT Co *MAPK-PP.Co *46 addmsg /kinetics/MAPK/MAPK /graphs/conc1/MAPK.Co PLOT Co *MAPK.Co *35 addmsg /kinetics/MAPK/Ras-MKKKK /graphs/conc2/Ras-MKKKK.Co PLOT Co *Ras-MKKKK.Co *47 addmsg /kinetics/MAPK/MAPK /graphs/conc2/MAPK.Co PLOT Co *MAPK.Co *35 addmsg /kinetics/MAPK/MKKK /graphs/conc2/MKKK.Co PLOT Co *MKKK.Co *16 addmsg /kinetics/MAPK/MKK /graphs/conc2/MKK.Co PLOT Co *MKK.Co *60 enddump // End of dump call /kinetics/MAPK/notes LOAD \ "This is the oscillatory MAPK model from Kholodenko 2000" \ "Eur J. Biochem 267:1583-1588" \ "The original model is formulated in terms of idealized" \ "Michaelis-Menten enzymes and the enzyme-substrate complex" \ "concentrations are therefore assumed negligible. The" \ "current implementation of the model uses explicit enzyme" \ "reactions involving substrates and is therefore an" \ "approximation to the Kholodenko model. The approximation is" \ "greatly improved if the enzyme is flagged as Available" \ "which is an option in Kinetikit. This flag means that the" \ "enzyme protein concentration is not reduced even when it" \ "is involved in a complex. However, the substrate protein" \ "continues to participate in enzyme-substrate complexes" \ "and its concentration is therefore affected. Overall," \ "this model works almost the same as the Kholodenko model" \ "but the peak MAPK-PP amplitudes are a little reduced and" \ "the period of oscillations is about 10% longer." \ "If the enzymes are not flagged as Available then the" \ "oscillations commence only when the Km for enzyme 1" \ "is set to 0.1 uM." call /kinetics/MAPK/MAPK/notes LOAD \ "The total concn. of MAPK is 300nM " \ "from" \ "Kholodenko, 2000." call /kinetics/MAPK/MKKK/notes LOAD \ "The total concn. of MKKK is 100nM " \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/MKK/notes LOAD \ "The total concn. of MKK is 300nM " \ "from" \ "Kholodenko,2000" call /kinetics/MAPK/int1/notes LOAD \ "This is the intermediate enzyme which catalyses the " \ "dephosphorylation of MKKK-P to MKKK. The concentration" \ "is set to 1 nM based on" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/int1/2/notes LOAD \ "Km is 8nM and Vmax is 0.25nM.s-1 " \ "from" \ "Kholodenko, 2000." call /kinetics/MAPK/MKKK-P/notes LOAD \ "This is the phosphorylated form of MKKK which converts MKK" \ "to MKK-P and then to MKK-PP" \ "from" \ "Kholodenko, 2000." call /kinetics/MAPK/MKKK-P/3/notes LOAD \ "Km is 15 nM and Vmax is 0.025s-1" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/MKKK-P/4/notes LOAD \ "Km is 15nM and Vmax is 0.025s-1" \ "from " \ "Kholodenko, 2000." call /kinetics/MAPK/int3/notes LOAD \ "This intermediate enzyme catalyses the dephosphorylation of" \ "MKK-P to MKK. The concentration is 1nM" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/int3/6/notes LOAD \ "The Km is 15nM and the Vmax is 0.75nM.s-1" \ "from" \ "Kholodenko 2000." call /kinetics/MAPK/int5/notes LOAD \ "This catalyses the conversion of MAPK-P to MAPK. The " \ "concenration is 1nM." \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/int5/10/notes LOAD \ "The Km is 15nM and Vmax is 0.5nM.s-1" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/MKK-P/notes LOAD \ "This is the single phoshorylated form of MKK." \ "from" \ "Kholodenko, 2000." call /kinetics/MAPK/MAPK-P/notes LOAD \ "This is the single phopshorylated form of MAPK" \ "from" \ "Kholodenko, 2000." call /kinetics/MAPK/int2/notes LOAD \ "This intermediate enzyme which catalyses the dephosphorylation of" \ "MKK-PP to MKK-P. The concentration is 1nM." \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/int2/5/notes LOAD \ "The Km is 15nM and Vmax is 0.75nM.s-1 " \ "from" \ "Kholodenko, 2000" \ "" call /kinetics/MAPK/int4/notes LOAD \ "This intermediate enzyme catalyses the dephosphorylation of" \ "MAPK-PP to MAPK-P. The concentration is 1nM." \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/int4/9/notes LOAD \ "The Km is 15nM and Vmax is 0.5nM.s-1 " \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/Ras-MKKKK/notes LOAD \ "The concn. of Ras-MKKKK* is set to 1 nM implicitly" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/Ras-MKKKK/1/notes LOAD \ "The Km is 10nM and Vmax is 2.5nM sec^-1. We assume that" \ "there is 1 nM of the Ras-MKKKK." \ "From Kholodenko, 2000." \ "" \ "If the enzymes are not flagged as Available, then this" \ "Km should be set to 0.1 to obtain oscillations." call /kinetics/MAPK/inactiveRas-MKKK/notes LOAD \ "This is the inactive form of Ras-MKKK. Based on the" \ "reaction scheme from Kholodenko 2000, this is equivalent" \ "to a binding of the MAPK-PP to the Ras. The amount of" \ "Ras in the model is small enough that negligible amounts" \ "of MAPK are involved in this reaction. So it is a fair" \ "approximation to the negative feedback mechanism from" \ "Kholodenko, 2000." call /kinetics/MAPK/Neg_feedback/notes LOAD \ "From Kholodenko, 2000 Eur J Biochem 267" \ "the Kd is 9 nM. We use a rather fast Kf of 1/sec/uM" \ "so that equilibrium is maintained." \ "" call /kinetics/MAPK/MKK-PP/notes LOAD \ "This is the double phosphorylated and active form of MKK" \ "from" \ "Kholodenko, 2000" call /kinetics/MAPK/MKK-PP/7/notes LOAD \ "The Km is 15nM which is 0.015uM Vmax is 0.025s-1" \ "from" \ "Kholodenko, 2000." \ "" call /kinetics/MAPK/MKK-PP/8/notes LOAD \ "The Km is 15nM which is 0.015uM and Vmax is 0.025s-1" \ "from" \ "Kholodenko, 2000" \ "" call /kinetics/MAPK/MAPK-PP/notes LOAD \ "This is the double phosphorylated and active form of MAPK." \ "from" \ "Kholodenko, 2000." 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