In CaN knock out mice, decreasing phosphorylation of PLB allowed

In CaN knock out mice, decreasing phosphorylation of PLB allowed an increased level of inhibition of the SERCA pump, which MG132 mechanism resulted in poor muscle contraction and relaxation. However, it is unclear if this behavior is a result of other compensatory mechanisms such as decreased CaMKII expression or enhanced PLB to SERCA ratio. On the contrary, CaN has been reported to inhibit SERCA activity in isolated non failing human myocardium in vitro. Hence, we model the role of CaN in rate dependent inhibition of the SERCA pump via PLB dephosphorylation by allowing the rate constant for phosphorylation of PLB to be depen dent on available active CaN in the myoplasm. With increasing heart rates, B adrenergic stimulation results in increasing levels of cAMP in vivo, which in turn phosphorylates PLB via PKA, causing enhanced uptake by the SERCA pump.

Together, activity dependent recruitment of these CaMKII and cAMP mediated effects at high frequencies Inhibitors,Modulators,Libraries counter Inhibitors,Modulators,Libraries the effect of CaN as well as decreasing cardiac cycle duration on SR refilling. Electro mechanics Our model for cardiac Inhibitors,Modulators,Libraries contractile mechanics is based on the approximate model of cooperative activation and crossbridge cycling reported by Rice et al. with the fol lowing modifications the first order rate constants for the transformation of the troponintropomyosin regulatory complex from a crossbridge non permitting state to a crossbridge permitting state and vice versa are chosen as 500 s 1 and 50 s 1 respectively in order to reproduce results reported by Rice et al.

the B adrenergic agonist isopro terenol is known to cause a decrease in myofilament Ca2 sensitivity as a result of PKA mediated phosphorylation of troponin I at Ser23Ser24. Specifically, a two state Markovian model is added to allow Inhibitors,Modulators,Libraries cAMP dependent Inhibitors,Modulators,Libraries PKA mediated inter action between troponin I and the Ca2 binding regulatory site on troponin. As reported by Messer et al. the unphosphorylated form of TnI modulates the Ca2 affinity of the regulatory site on troponin. We model the effects of cAMP by allowing the cumulative activation rate constant for Ca2 binding to the troponin regulatory site to be a function of unphosphorylated TnIu, the availability of which is in turn dependent on the amount of present. the large Q10 values used by Rice et al. are decreased from 6. 25 to 2. 25 in order to reproduce temperature dependence of peak force developed in intact thin rat ventricular trabeculae.

The rate constants governing cross bridge kinetics are modeled as functions of to reproduce stimulation frequency dependent increase in contraction and relaxation rates. Although a calmodulin mediated pathway has been reported to be responsi ble for modulation of myofibrillar Ca2 sensitivity, we refrain from modeling this effect as the molecular mechanisms involved remain unresolved.

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