A novel potential signaling target for excitation–contraction coupling may be protein kinase C (PKC). PKC was reported to phosphorylate the L-type calcium channel, phospholamban (PLN), and possibly the ryanodine receptor (RyR) as well.37 However, the exact physiological significance of PKC phosphorylation of these calcium-handling regulators remains unknown. In the mouse heart AG-1478 price activation of PKCα suppresses sarcoplasmic reticulum calcium cycling by phosphorylating Inhibitors,research,lifescience,medical protein phosphatase inhibitor 1. Hearts of PKCα-deficient mice are hypercontractile, whereas those of transgenic mice overexpressing

PKCα are hypocontractile.38 A study showed that phosphorylated phosphatase inhibitor 1 dissociated from protein phosphatase-1 and -2A and the resulting enhanced protein dephosphorylation activity lowered the phosphorylation level of PLN. Similarly short-term pharmacological inhibition of the conventional PKC isoforms significantly augmented cardiac contractility Inhibitors,research,lifescience,medical in wild-type mice and in different models of heart failure in vivo, but not Inhibitors,research,lifescience,medical in PKCα-deficient mice.39 Thus, PKCα functions as a nodal integrator of cardiac contractility by sensing intracellular calcium

and signal transduction events, which can modify contractility. PKCα inhibitors are available and have shown benefit in animal models. Further studies are needed in order to assess the potential use of a PKC inhibitor in the failing heart. A different approach to improve excitation–contraction coupling would be to improve force generation without altering the calcium transient in the myocyte. Stimulation of the myosin ATPase is expected

to accelerate the release Inhibitors,research,lifescience,medical of the weak actin–myosin cross-bridge Inhibitors,research,lifescience,medical and promotes transition to the force-producing state of the cross-bridge.35 As more cross-bridges are activated the contractile force increases. Indeed several such myosin ATPase-stimulatory agents were demonstrated to increase the fractional shortening of myocytes without increasing the intracellular calcium transients. In initial studies in dog models of heart failure, one such molecule, why omecamtiv mecarbil, increased stroke volume and cardiac output and decreased LV end-diastolic pressure and heart rate without increasing myocardial oxygen demand.40 Omecamtiv mecarbil binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state and accelerates actin-dependent phosphate release, which is the rate-limiting step in the actin–myosin ATPase cycle in cardiomyocytes.41 In small clinical studies omecamtiv mecarbil infusion resulted in dose- and concentration-dependent increases in stroke volume, fractional shortening, and ejection fraction.