This model is a superset of the PKC model presented in <a href = "http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9888852&dopt=Abstract ">Bhalla US and Iyengar R. Science (1999) 283(5400):381-7</a>. The current version includes PKC turnover. This version includes the stimulating pools Ca, AA and DAG as well as the PKC activity within the synaptic signaling pathway since it is meant to be a self-contained pathway model rather than part of network. Thu Nov 9 16:24:55 2006 pathway Upinder S. Bhalla, NCBS Upinder S. Bhalla, NCBS Genericl Mammalian Brain - Neuronal Cell membrane + Cytosol Quantitative match to experiments, Qualitative Exact GENESIS implementation Approximates original data This represents the ubiquitination and eventual removal of the PKC. See Lu et al 1998 Mol Cell 18(2):839-845 Just a unity concentration for convenience. The rate limiting step is the reaction. $\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_AA\_star\_}+\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_memb\_star\_}+\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_AA\_star\_}+\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_memb\_star\_}+\mathrm{PKC\_slash\_PKC\_minus\_basal\_star\_}+\mathrm{PKC\_slash\_PKC\_minus\_AA\_star\_}$ 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. kf*PKC_slash_PKC_minus_cytosolic*PKC_slash_Ca-kb*PKC_slash_PKC_minus_Ca $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_cytosolic}\mathrm{PKC\_slash\_Ca}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_Ca}$ 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 PKC. kf*PKC_slash_DAG*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_DAG $\mathrm{kf}\mathrm{PKC\_slash\_DAG}\mathrm{PKC\_slash\_PKC\_minus\_Ca}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_DAG}$ 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 activation. kf*PKC_slash_PKC_minus_Ca-kb*PKC_slash_PKC_minus_Ca_minus_memb_star_ $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_Ca}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_memb\_star\_}$ 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 notes. kf*PKC_slash_PKC_minus_Ca_minus_DAG-kb*PKC_slash_PKC_minus_DAG_minus_memb_star_ $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_DAG}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_memb\_star\_}$ 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 13(10):4361 kf*PKC_slash_PKC_minus_Ca*PKC_slash_AA-kb*PKC_slash_PKC_minus_Ca_minus_AA_star_ $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_Ca}\mathrm{PKC\_slash\_AA}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_AA\_star\_}$ 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 5149-5153 kf*PKC_slash_PKC_minus_DAG_minus_AA-kb*PKC_slash_PKC_minus_DAG_minus_AA_star_ $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_AA}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_AA\_star\_}$ 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 baseline. kf*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_basal_star_ $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_cytosolic}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_basal\_star\_}$ 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 translocation. kf*PKC_slash_AA*PKC_slash_PKC_minus_cytosolic-kb*PKC_slash_PKC_minus_AA_star_ $\mathrm{kf}\mathrm{PKC\_slash\_AA}\mathrm{PKC\_slash\_PKC\_minus\_cytosolic}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_AA\_star\_}$ 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 rate-limiting. kf*PKC_slash_PKC_minus_cytosolic*PKC_slash_DAG-kb*PKC_slash_PKC_minus_DAG $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_cytosolic}\mathrm{PKC\_slash\_DAG}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_DAG}$ 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 curves. kf*PKC_slash_PKC_minus_DAG*PKC_slash_AA-kb*PKC_slash_PKC_minus_DAG_minus_AA $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_DAG}\mathrm{PKC\_slash\_AA}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_AA}$ This rate is set up to balance the removal of PKC at resting PKC levels of about uM. kf*PKC_slash_PKC_minus_RNA-kb*PKC_slash_PKC_minus_cytosolic $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_RNA}-\mathrm{kb}\mathrm{PKC\_slash\_PKC\_minus\_cytosolic}$ 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 rate. kf*PKC_slash_PKC_minus_basal_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_basal\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ 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 rate. kf*PKC_slash_PKC_minus_Ca_minus_memb_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_memb\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ 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 rate. kf*PKC_slash_PKC_minus_DAG_minus_memb_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_memb\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ 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 rate. kf*PKC_slash_PKC_minus_Ca_minus_AA_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_Ca\_minus\_AA\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ 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 rate. kf*PKC_slash_PKC_minus_DAG_minus_AA_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_DAG\_minus\_AA\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ 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 rate. kf*PKC_slash_PKC_minus_AA_star_-kb*PKC_slash_degraded_minus_PKC $\mathrm{kf}\mathrm{PKC\_slash\_PKC\_minus\_AA\_star\_}-\mathrm{kb}\mathrm{PKC\_slash\_degraded\_minus\_PKC}$ Rate consts from Chen et al Biochem 32, 1032 (1993) Generic rates. k1*PKC_slash_PKC_minus_substrate*PKC_slash_PKC_minus_active-k2*PKC_slash_PKC_minus_active_slash_PKC_minus_enzyme_minus_activity_slash_PKC_minus_enzyme_minus_activity_cplx $\mathrm{k1}\mathrm{PKC\_slash\_PKC\_minus\_substrate}\mathrm{PKC\_slash\_PKC\_minus\_active}-\mathrm{k2}\mathrm{PKC\_slash\_PKC\_minus\_active\_slash\_PKC\_minus\_enzyme\_minus\_activity\_slash\_PKC\_minus\_enzyme\_minus\_activity\_cplx}$ k3*PKC_slash_PKC_minus_active_slash_PKC_minus_enzyme_minus_activity_slash_PKC_minus_enzyme_minus_activity_cplx $\mathrm{k3}\mathrm{PKC\_slash\_PKC\_minus\_active\_slash\_PKC\_minus\_enzyme\_minus\_activity\_slash\_PKC\_minus\_enzyme\_minus\_activity\_cplx}$