This is the model of CaMKII bistability, model 3. It exhibits bistability in CaMKII activation due to autophosphorylation at the PSD and local saturation of PP1. This version of model 3 does not include the full PKA regulatory pathway, and instead has a predefined initial amount of active PKA. Wed Aug 8 15:09:29 2007 network Upinder S. Bhalla, NCBS Arnold Hayer and Upinder S. Bhalla, NCBS General Mammalian Neuronal Synaptic Spine, Postsynaptic Density Quantitative match to experiments, Qualitative Exact GENESIS implementation Replicates original data , Qualitative predictions $\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}+\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286\_star\_\_minus\_CaM}$ $\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}+\mathrm{CaMKII\_slash\_CaMKII\_star\_\_star\_\_star\_}+\mathrm{basal\_CaMKII\_cyt}$ $\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}+\mathrm{CaMKII\_star\_\_star\_\_star\_\_minus\_PSD}+\mathrm{basal\_CaMKII\_PSD}$ $\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}+\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}$ $\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}+\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}+\mathrm{tot\_minus\_auto\_minus\_PSD}$ $\mathrm{actCaMKII\_minus\_PSD}+\mathrm{CaMKII\_minus\_PSD}+\mathrm{CaMKII\_minus\_thr305\_minus\_PSD}$ $\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}+\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286\_star\_\_minus\_CaM}+\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}+\mathrm{CaMKII\_slash\_CaMKII\_star\_\_star\_\_star\_}+\mathrm{CaMKII\_slash\_CaMK\_minus\_thr305}+\mathrm{CaMKII\_slash\_CaMKII}+\mathrm{basal\_CaMKII\_cyt}$ $\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII}+\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII}$ $\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}+\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}$ This is tricky. There is some cooperativity here arising from interactions between the subunits of the CAMKII holoenzyme. However, the stoichiometry is 1. Kb/Kf = 6e4 #/cell. Rate is fast (see Hanson et al Neuron 12 943-956 1994) so lets say kb = 10. This gives kf = 1.6667e-4 H&S AnnRev Biochem 92 give tau for dissoc as 0.2 sec at low Ca, 0.4 at high. Low Ca = 100 nM = physiol. kf*CaM_minus_Ca4*CaMKII_slash_CaMKII-kb*CaMKII_slash_CaMKII_minus_CaM $\mathrm{kf}\mathrm{CaM\_minus\_Ca4}\mathrm{CaMKII\_slash\_CaMKII}-\mathrm{kb}\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}$ Affinity is up 1000X. Time to release is about 20 sec, so the kb is OK at 0.1 This makes Kf around 1.6666e-3 kf*CaMKII_slash_CaMKII_minus_thr286*CaM_minus_Ca4-kb*CaMKII_slash_CaMKII_minus_thr286_star__minus_CaM $\mathrm{kf}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}\mathrm{CaM\_minus\_Ca4}-\mathrm{kb}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286\_star\_\_minus\_CaM}$ Lets use the fast rate consts here. Since the rates are so different, I am not sure whether the order is relevant. These correspond to the TR2C fragment. We use the Martin et al rates here, plus the Drabicowski binding consts. All are scaled by 3X to cell temp. kf = 2e-10 kb = 72 Stemmer & Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11. If kb=72, kf = 2e-10 (Exactly the same !).... kf*CaM_slash_CaM*Ca^2-kb*CaM_minus_TR2_minus_Ca2 $\mathrm{kf}\mathrm{CaM\_slash\_CaM}\mathrm{Ca}^2-\mathrm{kb}\mathrm{CaM\_minus\_TR2\_minus\_Ca2}$ K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10 kf*CaM_minus_TR2_minus_Ca2*Ca-kb*CaM_minus_Ca3 $\mathrm{kf}\mathrm{CaM\_minus\_TR2\_minus\_Ca2}\mathrm{Ca}-\mathrm{kb}\mathrm{CaM\_minus\_Ca3}$ Lets use the fast rate consts here. Since the rates are so different, I am not sure whether the order is relevant. These correspond to the TR2C fragment. We use the Martin et al rates here, plus the Drabicowski binding consts. All are scaled by 3X to cell temp. kf = 2e-10 kb = 72 Stemmer & Klee: K1=.9, K2=1.1. Assume 1.0uM for both. kb/kf=3.6e11. If kb=72, kf = 2e-10 (Exactly the same !).... kf*CaM_slash_CaM_minus_PSD*Ca_minus_PSD^2-kb*CaM_minus_TR2_minus_Ca2_minus_PSD $\mathrm{kf}\mathrm{CaM\_slash\_CaM\_minus\_PSD}\mathrm{Ca\_minus\_PSD}^2-\mathrm{kb}\mathrm{CaM\_minus\_TR2\_minus\_Ca2\_minus\_PSD}$ K3 = 21.5, K4 = 2.8. Assuming that the K4 step happens first, we get kb/kf = 2.8 uM = 1.68e6 so kf =6e-6 assuming kb = 10 kf*CaM_minus_TR2_minus_Ca2_minus_PSD*Ca_minus_PSD-kb*CaM_minus_Ca3_minus_PSD $\mathrm{kf}\mathrm{CaM\_minus\_TR2\_minus\_Ca2\_minus\_PSD}\mathrm{Ca\_minus\_PSD}-\mathrm{kb}\mathrm{CaM\_minus\_Ca3\_minus\_PSD}$ Use K3 = 21.5 uM here from Stemmer and Klee table 3. kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10 kf*CaM_minus_Ca3_minus_PSD*Ca_minus_PSD-kb*CaM_minus_Ca4_minus_PSD $\mathrm{kf}\mathrm{CaM\_minus\_Ca3\_minus\_PSD}\mathrm{Ca\_minus\_PSD}-\mathrm{kb}\mathrm{CaM\_minus\_Ca4\_minus\_PSD}$ K inhib = 1nM from Cohen Ann Rev Bioch 1989, 4 nM from Foukes et al Assume 2 nM. kf /kb = 8.333e-4 kf*PP1_slash_I1_star_*PP1_minus_active-kb*PP1_slash_PP1_minus_I1_star_ $\mathrm{kf}\mathrm{PP1\_slash\_I1\_star\_}\mathrm{PP1\_minus\_active}-\mathrm{kb}\mathrm{PP1\_slash\_PP1\_minus\_I1\_star\_}$ Let us assume that the equil in this case is very far over to the right. This is probably safe. kf*PP1_slash_PP1_minus_I1-kb*PP1_minus_active*PP1_slash_I1 $\mathrm{kf}\mathrm{PP1\_slash\_PP1\_minus\_I1}-\mathrm{kb}\mathrm{PP1\_minus\_active}\mathrm{PP1\_slash\_I1}$ This process is probably much more complicated and involves CaM. However, as I can\'t find detailed info I am bundling this into a single step. Based on Steemer and Klee pg 6863, the Kact is 0.5 uM. kf/kb = 1/(0.5 * 6e5)^2 = 1.11e-11 kf*Ca^2*PP2B_slash_CaNAB_minus_Ca2-kb*CaNAB_minus_Ca4 $\mathrm{kf}\mathrm{Ca}^2\mathrm{PP2B\_slash\_CaNAB\_minus\_Ca2}-\mathrm{kb}\mathrm{CaNAB\_minus\_Ca4}$ going on the experience with CaM, we put the fast (high affinity) sites first. We only know (Stemmer and Klee) that the affinity is < 70 nM. Assuming 10 nM at first, we get kf = 2.78e-8, kb = 1. Try 20 nM. kf = 7e-9, kb = 1 kf*PP2B_slash_CaNAB*Ca^2-kb*PP2B_slash_CaNAB_minus_Ca2 $\mathrm{kf}\mathrm{PP2B\_slash\_CaNAB}\mathrm{Ca}^2-\mathrm{kb}\mathrm{PP2B\_slash\_CaNAB\_minus\_Ca2}$ kf*CaM_minus_Ca4*CaNAB_minus_Ca4-kb*CaM_Ca_n_minus_CaNAB $\mathrm{kf}\mathrm{CaM\_minus\_Ca4}\mathrm{CaNAB\_minus\_Ca4}-\mathrm{kb}\mathrm{CaM\_Ca\_n\_minus\_CaNAB}$ kf*CaMKII_minus_PSD*CaM_minus_Ca4_minus_PSD-kb*CaMKII_minus_CaM_minus_PSD $\mathrm{kf}\mathrm{CaMKII\_minus\_PSD}\mathrm{CaM\_minus\_Ca4\_minus\_PSD}-\mathrm{kb}\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}$ Rates to match curve in fig2 from Shen and Meyer, Science 284:162-166(1999), calculated for 6:1 alpha:beta CaMKII heterodimers kf*CaMKII_slash_CaMKII_minus_CaM*NMDAR-kb*CaMKII_minus_CaM_minus_PSD $\mathrm{kf}\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}\mathrm{NMDAR}-\mathrm{kb}\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}$ Same as for transloc_1 kf*CaMKII_slash_CaMKII_minus_thr286_star__minus_CaM*NMDAR-kb*CaMKII_minus_thr286_minus_CaM_minus_PSD $\mathrm{kf}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286\_star\_\_minus\_CaM}\mathrm{NMDAR}-\mathrm{kb}\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}$ Rates set by the translocation experiments of Shen and Meyer, Science 1999. kf*CaMKII_minus_PSD-kb*CaMKII_slash_CaMKII*NMDAR $\mathrm{kf}\mathrm{CaMKII\_minus\_PSD}-\mathrm{kb}\mathrm{CaMKII\_slash\_CaMKII}\mathrm{NMDAR}$ Same as for back_1 kf*CaMKII_minus_thr305_minus_PSD-kb*CaMKII_slash_CaMK_minus_thr305*NMDAR $\mathrm{kf}\mathrm{CaMKII\_minus\_thr305\_minus\_PSD}-\mathrm{kb}\mathrm{CaMKII\_slash\_CaMK\_minus\_thr305}\mathrm{NMDAR}$ Same values as for the main compartment Can the main compartment pool of Ca/CaM be used? kf*CaMKII_minus_thr286_minus_PSD*CaM_minus_Ca4_minus_PSD-kb*CaMKII_minus_thr286_minus_CaM_minus_PSD $\mathrm{kf}\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}\mathrm{CaM\_minus\_Ca4\_minus\_PSD}-\mathrm{kb}\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}$ Diffusional equilibrium between PSD- and cytosolic compartment. According to D. Bary in Cell Movements 2nd ed 2001 D for proteins is 5e-7 cm^2/s giving 10 ms for a translocation of 1 um. kf*CaM_minus_Ca4_minus_PSD-kb*CaM_minus_Ca4 $\mathrm{kf}\mathrm{CaM\_minus\_Ca4\_minus\_PSD}-\mathrm{kb}\mathrm{CaM\_minus\_Ca4}$ Let us assume that the equil in this case is very far over to the right. This is probably safe. kf*PP1_PSD_slash_PP1_minus_I1-kb*PP1_PSD_slash_I1*PP1_minus_active_PSD $\mathrm{kf}\mathrm{PP1\_PSD\_slash\_PP1\_minus\_I1}-\mathrm{kb}\mathrm{PP1\_PSD\_slash\_I1}\mathrm{PP1\_minus\_active\_PSD}$ K inhib = 1nM from Cohen Ann Rev Bioch 1989, 4 nM from Foukes et al Assume 2 nM. kf /kb = 8.333e-4 kf*PP1_PSD_slash_I1_star_*PP1_minus_active_PSD-kb*PP1_PSD_slash_PP1_minus_I1_star_ $\mathrm{kf}\mathrm{PP1\_PSD\_slash\_I1\_star\_}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{kb}\mathrm{PP1\_PSD\_slash\_PP1\_minus\_I1\_star\_}$ Use K3 = 21.5 uM here from Stemmer and Klee table 3. kb/kf =21.5 * 6e5 so kf = 7.75e-7, kb = 10 kf*CaM_minus_Ca3*Ca-kb*CaM_minus_Ca4 $\mathrm{kf}\mathrm{CaM\_minus\_Ca3}\mathrm{Ca}-\mathrm{kb}\mathrm{CaM\_minus\_Ca4}$ kf*CaMKII_minus_CaM_minus_PSD-kb*CaM_minus_Ca4_minus_PSD*CaMKII_minus_PSD $\mathrm{kf}\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}-\mathrm{kb}\mathrm{CaM\_minus\_Ca4\_minus\_PSD}\mathrm{CaMKII\_minus\_PSD}$ kf*Ca_control_cyt-kb*Ca $\mathrm{kf}\mathrm{Ca\_control\_cyt}-\mathrm{kb}\mathrm{Ca}$ kf*Ca_control_PSD-kb*Ca_minus_PSD $\mathrm{kf}\mathrm{Ca\_control\_PSD}-\mathrm{kb}\mathrm{Ca\_minus\_PSD}$ kf*basal_CaMKII_PSD_control-kb*basal_CaMKII_PSD $\mathrm{kf}\mathrm{basal\_CaMKII\_PSD\_control}-\mathrm{kb}\mathrm{basal\_CaMKII\_PSD}$ k1*CaMKII_slash_CaMKII_minus_thr286_star__minus_CaM*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286\_star\_\_minus\_CaM}\mathrm{PP1\_minus\_active}-\mathrm{k2}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286\_slash\_Deph\_minus\_thr286\_cplx}$ k3*PP1_minus_active_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286\_slash\_Deph\_minus\_thr286\_cplx}$ k1*CaMKII_slash_CaMKII_minus_thr286*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr286b_slash_Deph_minus_thr286b_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}\mathrm{PP1\_minus\_active}-\mathrm{k2}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286b\_slash\_Deph\_minus\_thr286b\_cplx}$ k3*PP1_minus_active_slash_Deph_minus_thr286b_slash_Deph_minus_thr286b_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286b\_slash\_Deph\_minus\_thr286b\_cplx}$ k1*CaMKII_slash_CaMKII_star__star__star_*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_star\_\_star\_\_star\_}\mathrm{PP1\_minus\_active}-\mathrm{k2}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr305\_slash\_Deph\_minus\_thr305\_cplx}$ k3*PP1_minus_active_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr305\_slash\_Deph\_minus\_thr305\_cplx}$ k1*CaMKII_slash_CaMKII_star__star__star_*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_star\_\_star\_\_star\_}\mathrm{PP1\_minus\_active}-\mathrm{k2}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286c\_slash\_Deph\_minus\_thr286c\_cplx}$ k3*PP1_minus_active_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr286c\_slash\_Deph\_minus\_thr286c\_cplx}$ k1*CaMKII_slash_CaMK_minus_thr305*PP1_minus_active-k2*PP1_minus_active_slash_Deph_minus_thr305a_slash_Deph_minus_thr305a_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMK\_minus\_thr305}\mathrm{PP1\_minus\_active}-\mathrm{k2}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr305a\_slash\_Deph\_minus\_thr305a\_cplx}$ k3*PP1_minus_active_slash_Deph_minus_thr305a_slash_Deph_minus_thr305a_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_slash\_Deph\_minus\_thr305a\_slash\_Deph\_minus\_thr305a\_cplx}$ #s from Bramson et al CRC crit rev Biochem 15:2 93-124. They have a huge list of peptide substrates and I have chosen high-ish rates. These consts give too much PKA activity, so lower Vmax 1/3. Now, k1 = 3e-5, k2 = 36, k3 = 9 (still pretty fast). Also lower Km 1/3 so k1 = 1e-5 Cohen et al FEBS Lett 76:182-86 1977 say rate =30% PKA act on phosphokinase beta. k1*PP1_slash_I1*PKA_minus_active-k2*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_slash_PKA_minus_phosph_minus_I1_cplx $\mathrm{k1}\mathrm{PP1\_slash\_I1}\mathrm{PKA\_minus\_active}-\mathrm{k2}\mathrm{PKA\_minus\_active\_slash\_PKA\_minus\_phosph\_minus\_I1\_slash\_PKA\_minus\_phosph\_minus\_I1\_cplx}$ k3*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_slash_PKA_minus_phosph_minus_I1_cplx $\mathrm{k3}\mathrm{PKA\_minus\_active\_slash\_PKA\_minus\_phosph\_minus\_I1\_slash\_PKA\_minus\_phosph\_minus\_I1\_cplx}$ k1*PP1_PSD_slash_I1*PKA_minus_active-k2*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_PSD_slash_PKA_minus_phosph_minus_I1_PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_I1}\mathrm{PKA\_minus\_active}-\mathrm{k2}\mathrm{PKA\_minus\_active\_slash\_PKA\_minus\_phosph\_minus\_I1\_PSD\_slash\_PKA\_minus\_phosph\_minus\_I1\_PSD\_cplx}$ k3*PKA_minus_active_slash_PKA_minus_phosph_minus_I1_PSD_slash_PKA_minus_phosph_minus_I1_PSD_cplx $\mathrm{k3}\mathrm{PKA\_minus\_active\_slash\_PKA\_minus\_phosph\_minus\_I1\_PSD\_slash\_PKA\_minus\_phosph\_minus\_I1\_PSD\_cplx}$ Rates from autocamtide phosphorylation, from Hanson and Schulman JBC 267:24 17216-17224 1992. Jan 1 1998: Speed up 12x to match fig 5. k1*CaMKII_slash_CaMKII_minus_thr286*CaMKII_slash_tot_CaM_CaMKII-k2*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_305_slash_CaM_act_305_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII}-\mathrm{k2}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII\_slash\_CaM\_act\_305\_slash\_CaM\_act\_305\_cplx}$ k3*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_305_slash_CaM_act_305_cplx $\mathrm{k3}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII\_slash\_CaM\_act\_305\_slash\_CaM\_act\_305\_cplx}$ k1*CaMKII_slash_CaMKII_minus_CaM*CaMKII_slash_tot_CaM_CaMKII-k2*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_286_slash_CaM_act_286_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII}-\mathrm{k2}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII\_slash\_CaM\_act\_286\_slash\_CaM\_act\_286\_cplx}$ k3*CaMKII_slash_tot_CaM_CaMKII_slash_CaM_act_286_slash_CaM_act_286_cplx $\mathrm{k3}\mathrm{CaMKII\_slash\_tot\_CaM\_CaMKII\_slash\_CaM\_act\_286\_slash\_CaM\_act\_286\_cplx}$ See Hanson and Schulman again, for afterburst rates of phosph. k1*CaMKII_slash_CaMKII_minus_thr286*CaMKII_slash_tot_autonomous_CaMKII-k2*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_305_slash_auton_305_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_thr286}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII}-\mathrm{k2}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII\_slash\_auton\_305\_slash\_auton\_305\_cplx}$ k3*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_305_slash_auton_305_cplx $\mathrm{k3}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII\_slash\_auton\_305\_slash\_auton\_305\_cplx}$ k1*CaMKII_slash_CaMKII_minus_CaM*CaMKII_slash_tot_autonomous_CaMKII-k2*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_286_slash_auton_286_cplx $\mathrm{k1}\mathrm{CaMKII\_slash\_CaMKII\_minus\_CaM}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII}-\mathrm{k2}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII\_slash\_auton\_286\_slash\_auton\_286\_cplx}$ k3*CaMKII_slash_tot_autonomous_CaMKII_slash_auton_286_slash_auton_286_cplx $\mathrm{k3}\mathrm{CaMKII\_slash\_tot\_autonomous\_CaMKII\_slash\_auton\_286\_slash\_auton\_286\_cplx}$ PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989. For now, lets halve Km. k1 was 3.3e-6, now 6.6e-6 k1*PP1_slash_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_I1_slash_PP2A_minus_dephosph_minus_I1_cplx $\mathrm{k1}\mathrm{PP1\_slash\_I1\_star\_}\mathrm{PP2A}-\mathrm{k2}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_cplx}$ k3*PP2A_slash_PP2A_minus_dephosph_minus_I1_slash_PP2A_minus_dephosph_minus_I1_cplx $\mathrm{k3}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_cplx}$ k1 changed from 3.3e-6 to 6.6e-6 k1*PP1_slash_PP1_minus_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__cplx $\mathrm{k1}\mathrm{PP1\_slash\_PP1\_minus\_I1\_star\_}\mathrm{PP2A}-\mathrm{k2}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_cplx}$ k3*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__cplx $\mathrm{k3}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_cplx}$ PP2A does most of the dephosph of I1 at basal Ca levels. See the review by Cohen in Ann Rev Biochem 1989. For now, lets halve Km. k1 was 3.3e-6, now 6.6e-6 k1*PP1_PSD_slash_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_I1_PSD_slash_PP2A_minus_dephosph_minus_I1_PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_I1\_star\_}\mathrm{PP2A}-\mathrm{k2}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_PSD\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_PSD\_cplx}$ k3*PP2A_slash_PP2A_minus_dephosph_minus_I1_PSD_slash_PP2A_minus_dephosph_minus_I1_PSD_cplx $\mathrm{k3}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_PSD\_slash\_PP2A\_minus\_dephosph\_minus\_I1\_PSD\_cplx}$ k1 changed from 3.3e-6 to 6.6e-6 k1*PP1_PSD_slash_PP1_minus_I1_star_*PP2A-k2*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__PSD_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_PP1\_minus\_I1\_star\_}\mathrm{PP2A}-\mathrm{k2}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_cplx}$ k3*PP2A_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__PSD_slash_PP2A_minus_dephosph_minus_PP1_minus_I_star__PSD_cplx $\mathrm{k3}\mathrm{PP2A\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_slash\_PP2A\_minus\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_cplx}$ The rates here are so slow I do not know if we should even bother with this enz reacn. These numbers are from Liu and Storm. Other refs suggest that the Km stays the same but the Vmax goes to 10% of the CaM stim levels. Prev: k1=2.2e-9, k2 = 0.0052, k3 = 0.0013 New : k1=5.7e-8, k2=.136, k3=.034 k1*PP1_slash_I1_star_*CaNAB_minus_Ca4-k2*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_slash_dephosph_inhib1_noCaM_cplx $\mathrm{k1}\mathrm{PP1\_slash\_I1\_star\_}\mathrm{CaNAB\_minus\_Ca4}-\mathrm{k2}\mathrm{CaNAB\_minus\_Ca4\_slash\_dephosph\_inhib1\_noCaM\_slash\_dephosph\_inhib1\_noCaM\_cplx}$ k3*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_slash_dephosph_inhib1_noCaM_cplx $\mathrm{k3}\mathrm{CaNAB\_minus\_Ca4\_slash\_dephosph\_inhib1\_noCaM\_slash\_dephosph\_inhib1\_noCaM\_cplx}$ The rates here are so slow I do not know if we should even bother with this enz reacn. These numbers are from Liu and Storm. Other refs suggest that the Km stays the same but the Vmax goes to 10% of the CaM stim levels. Prev: k1=2.2e-9, k2 = 0.0052, k3 = 0.0013 New : k1=5.7e-8, k2=.136, k3=.034 k1*PP1_PSD_slash_I1_star_*CaNAB_minus_Ca4-k2*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_PSD_slash_dephosph_inhib1_noCaM_PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_I1\_star\_}\mathrm{CaNAB\_minus\_Ca4}-\mathrm{k2}\mathrm{CaNAB\_minus\_Ca4\_slash\_dephosph\_inhib1\_noCaM\_PSD\_slash\_dephosph\_inhib1\_noCaM\_PSD\_cplx}$ k3*CaNAB_minus_Ca4_slash_dephosph_inhib1_noCaM_PSD_slash_dephosph_inhib1_noCaM_PSD_cplx $\mathrm{k3}\mathrm{CaNAB\_minus\_Ca4\_slash\_dephosph\_inhib1\_noCaM\_PSD\_slash\_dephosph\_inhib1\_noCaM\_PSD\_cplx}$ k1*CaMKII_minus_thr286_minus_PSD*tot_minus_auto_minus_PSD-k2*tot_minus_auto_minus_PSD_slash_auton_minus_305_minus_PSD_slash_auton_minus_305_minus_PSD_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}\mathrm{tot\_minus\_auto\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_305\_minus\_PSD\_slash\_auton\_minus\_305\_minus\_PSD\_cplx}$ k3*tot_minus_auto_minus_PSD_slash_auton_minus_305_minus_PSD_slash_auton_minus_305_minus_PSD_cplx $\mathrm{k3}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_305\_minus\_PSD\_slash\_auton\_minus\_305\_minus\_PSD\_cplx}$ k1*CaMKII_minus_CaM_minus_PSD*tot_minus_auto_minus_PSD-k2*tot_minus_auto_minus_PSD_slash_auton_minus_286_minus_PSD_slash_auton_minus_286_minus_PSD_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}\mathrm{tot\_minus\_auto\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_286\_minus\_PSD\_slash\_auton\_minus\_286\_minus\_PSD\_cplx}$ k3*tot_minus_auto_minus_PSD_slash_auton_minus_286_minus_PSD_slash_auton_minus_286_minus_PSD_cplx $\mathrm{k3}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_286\_minus\_PSD\_slash\_auton\_minus\_286\_minus\_PSD\_cplx}$ k1*CaMKII_minus_PSD*tot_minus_auto_minus_PSD-k2*tot_minus_auto_minus_PSD_slash_auton_minus_autoph_slash_auton_minus_autoph_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_PSD}\mathrm{tot\_minus\_auto\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_autoph\_slash\_auton\_minus\_autoph\_cplx}$ k3*tot_minus_auto_minus_PSD_slash_auton_minus_autoph_slash_auton_minus_autoph_cplx $\mathrm{k3}\mathrm{tot\_minus\_auto\_minus\_PSD\_slash\_auton\_minus\_autoph\_slash\_auton\_minus\_autoph\_cplx}$ k1*CaMKII_minus_thr286_minus_CaM_minus_PSD*PP1_minus_active_PSD-k2*PP1_minus_active_PSD_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_thr286\_minus\_CaM\_minus\_PSD}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{k2}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286\_slash\_Deph\_minus\_thr286\_cplx}$ k3*PP1_minus_active_PSD_slash_Deph_minus_thr286_slash_Deph_minus_thr286_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286\_slash\_Deph\_minus\_thr286\_cplx}$ k1*CaMKII_minus_thr286_minus_PSD*PP1_minus_active_PSD-k2*PP1_minus_active_PSD_slash_Deph_minus_thr286b_slash_Deph_minus_thr286b_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{k2}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286b\_slash\_Deph\_minus\_thr286b\_cplx}$ k3*PP1_minus_active_PSD_slash_Deph_minus_thr286b_slash_Deph_minus_thr286b_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286b\_slash\_Deph\_minus\_thr286b\_cplx}$ k1*CaMKII_star__star__star__minus_PSD*PP1_minus_active_PSD-k2*PP1_minus_active_PSD_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx $\mathrm{k1}\mathrm{CaMKII\_star\_\_star\_\_star\_\_minus\_PSD}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{k2}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286c\_slash\_Deph\_minus\_thr286c\_cplx}$ k3*PP1_minus_active_PSD_slash_Deph_minus_thr286c_slash_Deph_minus_thr286c_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr286c\_slash\_Deph\_minus\_thr286c\_cplx}$ k1*CaMKII_minus_thr305_minus_PSD*PP1_minus_active_PSD-k2*PP1_minus_active_PSD_slash_Deph_minus_thr305a_slash_Deph_minus_thr305a_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_thr305\_minus\_PSD}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{k2}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr305a\_slash\_Deph\_minus\_thr305a\_cplx}$ k3*PP1_minus_active_PSD_slash_Deph_minus_thr305a_slash_Deph_minus_thr305a_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr305a\_slash\_Deph\_minus\_thr305a\_cplx}$ k1*CaMKII_star__star__star__minus_PSD*PP1_minus_active_PSD-k2*PP1_minus_active_PSD_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx $\mathrm{k1}\mathrm{CaMKII\_star\_\_star\_\_star\_\_minus\_PSD}\mathrm{PP1\_minus\_active\_PSD}-\mathrm{k2}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr305\_slash\_Deph\_minus\_thr305\_cplx}$ k3*PP1_minus_active_PSD_slash_Deph_minus_thr305_slash_Deph_minus_thr305_cplx $\mathrm{k3}\mathrm{PP1\_minus\_active\_PSD\_slash\_Deph\_minus\_thr305\_slash\_Deph\_minus\_thr305\_cplx}$ k1*PP1_slash_I1_star_*CaM_Ca_n_minus_CaNAB-k2*CaM_Ca_n_minus_CaNAB_slash_dephosph_inhib1_slash_dephosph_inhib1_cplx $\mathrm{k1}\mathrm{PP1\_slash\_I1\_star\_}\mathrm{CaM\_Ca\_n\_minus\_CaNAB}-\mathrm{k2}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_inhib1\_slash\_dephosph\_inhib1\_cplx}$ k3*CaM_Ca_n_minus_CaNAB_slash_dephosph_inhib1_slash_dephosph_inhib1_cplx $\mathrm{k3}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_inhib1\_slash\_dephosph\_inhib1\_cplx}$ k1*PP1_slash_PP1_minus_I1_star_*CaM_Ca_n_minus_CaNAB-k2*CaM_Ca_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__slash_dephosph_minus_PP1_minus_I_star__cplx $\mathrm{k1}\mathrm{PP1\_slash\_PP1\_minus\_I1\_star\_}\mathrm{CaM\_Ca\_n\_minus\_CaNAB}-\mathrm{k2}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_cplx}$ k3*CaM_Ca_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__slash_dephosph_minus_PP1_minus_I_star__cplx $\mathrm{k3}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_cplx}$ k1*PP1_PSD_slash_I1_star_*CaM_Ca_n_minus_CaNAB-k2*CaM_Ca_n_minus_CaNAB_slash_dephosph_inhib1_PSD_slash_dephosph_inhib1_PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_I1\_star\_}\mathrm{CaM\_Ca\_n\_minus\_CaNAB}-\mathrm{k2}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_inhib1\_PSD\_slash\_dephosph\_inhib1\_PSD\_cplx}$ k3*CaM_Ca_n_minus_CaNAB_slash_dephosph_inhib1_PSD_slash_dephosph_inhib1_PSD_cplx $\mathrm{k3}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_inhib1\_PSD\_slash\_dephosph\_inhib1\_PSD\_cplx}$ k1*PP1_PSD_slash_PP1_minus_I1_star_*CaM_Ca_n_minus_CaNAB-k2*CaM_Ca_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__PSD_slash_dephosph_minus_PP1_minus_I_star__PSD_cplx $\mathrm{k1}\mathrm{PP1\_PSD\_slash\_PP1\_minus\_I1\_star\_}\mathrm{CaM\_Ca\_n\_minus\_CaNAB}-\mathrm{k2}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_cplx}$ k3*CaM_Ca_n_minus_CaNAB_slash_dephosph_minus_PP1_minus_I_star__PSD_slash_dephosph_minus_PP1_minus_I_star__PSD_cplx $\mathrm{k3}\mathrm{CaM\_Ca\_n\_minus\_CaNAB\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_slash\_dephosph\_minus\_PP1\_minus\_I\_star\_\_PSD\_cplx}$ k1*CaMKII_minus_thr286_minus_PSD*tot_minus_CaM_minus_CaMKII_minus_PSD-k2*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_minus_act_minus_305_minus_PSD_slash_CaM_minus_act_minus_305_minus_PSD_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_thr286\_minus\_PSD}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_305\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_305\_minus\_PSD\_cplx}$ k3*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_minus_act_minus_305_minus_PSD_slash_CaM_minus_act_minus_305_minus_PSD_cplx $\mathrm{k3}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_305\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_305\_minus\_PSD\_cplx}$ k1*CaMKII_minus_CaM_minus_PSD*tot_minus_CaM_minus_CaMKII_minus_PSD-k2*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_minus_act_minus_286_minus_PSD_slash_CaM_minus_act_minus_286_minus_PSD_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_CaM\_minus\_PSD}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_286\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_286\_minus\_PSD\_cplx}$ k3*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_minus_act_minus_286_minus_PSD_slash_CaM_minus_act_minus_286_minus_PSD_cplx $\mathrm{k3}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_286\_minus\_PSD\_slash\_CaM\_minus\_act\_minus\_286\_minus\_PSD\_cplx}$ k1*CaMKII_minus_PSD*tot_minus_CaM_minus_CaMKII_minus_PSD-k2*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_act_autoph_slash_CaM_act_autoph_cplx $\mathrm{k1}\mathrm{CaMKII\_minus\_PSD}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD}-\mathrm{k2}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_act\_autoph\_slash\_CaM\_act\_autoph\_cplx}$ k3*tot_minus_CaM_minus_CaMKII_minus_PSD_slash_CaM_act_autoph_slash_CaM_act_autoph_cplx $\mathrm{k3}\mathrm{tot\_minus\_CaM\_minus\_CaMKII\_minus\_PSD\_slash\_CaM\_act\_autoph\_slash\_CaM\_act\_autoph\_cplx}$