The subcellular localization of neuronal nitric oxide synthase determines the downstream effects of NO on myocardial function

Aims In healthy hearts, the neuronal nitric oxide synthase (nNOS) is predominantly localized to the sarcoplasmic reticulum (SR), where it regulates the ryanodine receptor Ca2+ release channel (RyR2) and phospholamban (PLB) phosphorylation, and to a lesser extent to the sarcolemmal membrane where it inhibits the L-type Ca2+ current (I-Ca). However, in failing hearts, impaired relaxation and depressed inotropy are associated with a larger proportion of nNOS being localized to the sarcolemmal membrane. Whether there is a causal relationship between altered myocardial function and subcellular localization of nNOS remains to be assessed.