//genesis // kkit Version 8 flat dumpfile // Saved on Tue Jan 22 09:11:24 2002 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 = 8.0 setfield /file/modpath value /home2/bhalla/scripts/modules kparms //genesis initdump -version 3 -ignoreorphans 1 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 kpool CoTotal CoInit Co n nInit nTotal nMin vol slave_enable notes \ 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 proto x y z simobjdump linkinfo xtree_fg_req xtree_textfg_req uplink downlink x y z simobjdump uplink xtree_fg_req xtree_textfg_req x y z simobjdump downlink xtree_fg_req xtree_textfg_req x y z simobjdump mirror notes xtree_fg_req x y z 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 0.28282 3.7208e-17 3.7208e-17 \ 2.2325e-11 2.2325e-11 1.6969e+05 0 6e+05 0 "" 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 0.12061 0 0 0 0 72366 0 6e+05 0 \ "" cyan blue 2 7 0 simundump kpool /kinetics/PKC/PKC-Ca-AA* 0 0.16962 0 0 0 0 1.0177e+05 0 6e+05 \ 0 "" orange blue -2 7 0 simundump kpool /kinetics/PKC/PKC-Ca-memb* 0 0.10258 0 0 0 0 61549 0 6e+05 0 \ "" pink blue -4 7 0 simundump kpool /kinetics/PKC/PKC-DAG-memb* 0 0.023753 0 0 0 0 14252 0 6e+05 \ 0 "" yellow blue 4 7 0 simundump kpool /kinetics/PKC/PKC-basal* 0 0.0432 0 0 0 0 25920 0 6e+05 0 "" \ 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 1 0 0 0 0 6e+05 0 6e+05 0 "" 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 0.0017993 8.4632e-23 8.4632e-23 \ 5.0779e-17 5.0779e-17 1079.6 0 6e+05 0 "" 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 0.08533 0 0 0 0 51198 0 6e+05 0 "" \ 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 0.012093 2.5188e-19 2.5188e-19 \ 1.5113e-13 1.5113e-13 7255.5 0 6e+05 0 "" white blue 2 1 0 simundump kpool /kinetics/PKC/PKC-cytosolic 0 1.5489 1 1 6e+05 6e+05 \ 9.2935e+05 0 6e+05 0 "" white blue -2 -5 0 simundump kpool /kinetics/PKC/degraded-PKC 0 0 0 0 0 0 0 0 6e+05 4 "" 27 blue \ -1 13 0 simundump kpool /kinetics/PKC/PKC-RNA 0 1 1 1 6e+05 6e+05 6e+05 0 6e+05 4 "" \ 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 0 0 0 0 6e+05 2 "" 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 0.08 0.08 0.08 48000 48000 48000 0 6e+05 0 \ "" red blue -4 -5 0 simundump kpool /kinetics/PKC/AA 0 1 5.5 0 0 3.3e+06 6e+05 0 6e+05 0 "" \ darkgreen blue 0 -5 0 simundump kpool /kinetics/PKC/DAG 1 1.6667e-06 11.66 0 0 6.996e+06 1 0 6e+05 \ 0 "" green blue 2 -5 0 simundump kpool /kinetics/PKC/PKC-substrate 0 0 0 0 0 0 0 0 6e+05 0 "" blue \ blue 4 13 0 simundump kpool /kinetics/PKC/PKC-substrate* 0 0 0 0 0 0 0 0 6e+05 0 "" 60 \ blue 6 13 0 simundump xgraph /graphs/conc1 0 0 4000 0 51.483 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 xplot /graphs/conc1/nuc_MAPK*.Co 3 524288 \ "delete_plot.w ; edit_plot.D " 47 0 0 1 simundump xplot /graphs/conc2/PDGFR.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xplot /graphs/conc2/PDGF.Co 3 524288 \ "delete_plot.w ; edit_plot.D " red 0 0 1 simundump xgraph /moregraphs/conc3 0 0 13040 0 1 0 simundump xgraph /moregraphs/conc4 0 0 13040 0 1 0 simundump xcoredraw /edit/draw 0 -8 8 -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." complete_loading