Cardiovascular Research Advance Access first published online on September 18, 2007
This version published online on October 16, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm012
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Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation–contraction coupling
1 Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
2 Unit of Cardiac Physiology, University of Manchester, 3.18 Core Technology Facility, 46 Grafton Street, Manchester, M13 9NT, UK
* Corresponding author. Tel: +44 1865 220132; fax: +44 1865 768844. E-mail address: barbara.casadei{at}cardiov.ox.ac.uk
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 Ca2+ 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 Ca2+ 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 (Popen). 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 Ca2+ leak, depleted SR Ca2+ store, and reduced contractility in heart failure.
KEYWORDS nitric oxide, e-c coupling; calcium (cellular); SR (function); transgenic animal models
Time for primary review: 14 days
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