Differential effects of S100 proteins A2 and A6 on cardiac Ca(2+) cycling and contractile performance.

Defective intracellular calcium (Ca(2+)) handling is implicated in the pathogenesis of heart failure. Novel approaches targeting both cardiac Ca(2+) release and reuptake processes, such as S100A1, have the potential to rescue the function of failing cardiac myocytes. Here, we show that two members of the S100 Ca(2+) binding protein family, S100A2 and S100A6 that share high sequence homology, differentially influence cardiac Ca(2+) handling and contractility. Cardiac gene expression of S100A2 significantly enhanced both contractile and relaxation performance of rodent and canine cardiac myocytes, mimicking the functional effects of its cardiac homologue, S100A1. To interrogate mechanism, Ca(2+) spark frequency, a measure of the gating of the ryanodine receptor Ca(2+) release channel, was found to be significantly increased by S100A2. Therapeutic testing showed that S100A2 rescued the contractile defects of failing cardiac myocytes. In contrast, cardiac expression of S100A6 had no significant effects on contractility or Ca(2+) handling. These data reveal novel differential effects of S100 proteins on cardiac myocyte performance that may be useful in application to diseased cardiac muscle.