In a recent article, MacDonnell et al. reported that protein kinase A (PKA) phosphorylation of ryanodine receptor (RyR2) (the Ca2+ release channel of the sarcoplasmic reticulum [SR]) at Ser2808/09 site does not have a major role in the sympathetic nervous system (SNS) regulation of cardiac function. This conclusion was based on comparing the effect of isoproterenol on ventricular performance, in vivo, in isolated hearts and myocytes, in wild-type mice and in a genetically modified mouse in which Ser2808 of RyR2 was replaced by alanine (S2808A) to prevent PKA-mediated phosphorylation at this site. Isoproterenol produced an increase in cardiac function both in vivo and in isolated hearts, as well as an enhancement in the L-type Ca2+ current ( I CaL), the amplitude of the Ca2+ transient and the excitation–contraction coupling (ECC) gain in isolated myocytes, which were not significantly different between wild-type and …