Why Is There SR Ca Release at Negative Potentials in Failing Human Ventricular Myocytes Under Control Conditions?
ICa,L-induced SR Ca release was observed in human myocytes at negative test potentials in the absence of added PKA activators. This is surprising because SR Ca loading is substantially reduced in failing human myocytes. 38 Although this observation could represent a fundamental difference in Ca channel behavior in human and feline myocytes, it might also be the result of an increased level of basal L-type Ca channel 39 and or RyR 40 channel phosphorylation in failing human ventricular myocytes that modify EC coupling. Along these lines, PKA-mediated phosphorylation of Na channels causes a leftward shift in the voltage-dependence of activation. 16,17 We found that ISO had substantially smaller effects on the voltage-dependence of Na channel activation in failing human myocytes than in feline cells (Figure 1), consistent with the effects of increased basal phosphorylation.
