Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation-contraction coupling.
Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation-contraction coupling (ECC), and here we discuss the evidence that NO may modulate the function of the ryanodine receptor Ca(2+) release channel (RyR2) on the cardiac sarcoplasmic reticulum (SR). Both constitutive isoforms of NOS have been shown to co-immunoprecipitate with RyR2, suggesting that the channel may be a target protein for NO. eNOS gene deletion has been shown to abolish the increase in spontaneous Ca(2+) spark frequency in cardiomyocytes exposed to sustained stretch, whereas the effect of nNOS-derived NO on RyR2 function remains to be investigated. Single channel studies have been performed with RyR2 reconstituted in planar lipid bilayers and exposed to various NO donors and, under these conditions, NO appears to have a dose-dependent, stimulatory effect on channel open probability (P(open)). We discuss whether NO has a direct effect on RyR2 via covalent S-nitrosylation of reactive thiol residues within the protein, or whether there are downstream effects via cyclic nucleotides, phosphodiesterases, and protein kinases. Finally, we consider whether the proposed migration of nNOS from the SR to the sarcolemma in the failing heart may have consequences for the nitrosative vs. oxidative balance at the level of the RyR2, and whether this may contribute to an increased diastolic Ca(2+) leak, depleted SR Ca(2+) store, and reduced contractility in heart failure.
Lim
Gregory
G
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Venetucci
Luigi
L
Eisner
David A
DA
Casadei
Barbara
B
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D010084:Oxidation-Reduction; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel; D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; D006152:Cyclic GMP; D002118:Calcium