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Phosphorylated ryanodine receptors open more often (bottom) and may lead to decreased exercise tolerance.

Patients with heart failure often have reduced exercise tolerance that cannot be explained solely by their impaired blood flow. On page 919, Reiken et al. identify the molecular defect that may underlie this phenomenon, revealing promising therapeutic targets and supporting a new model for the pathogenesis of this widespread disease.

Coupling of excitation and contraction in skeletal muscle requires the type 1 ryanodine receptor (RyR1), a calcium channel that forms a complex with several regulatory proteins. The authors identified a unique site on RyR1 that is phosphorylated by protein kinase A; they then generated mutant channels that either cannot be phosphorylated or that mimic constitutively phosphorylated RyR1. Phosphorylation of the channel causes it to dissociate from the regulatory protein FKBP12, allowing the channel to open more frequently. Compared with RyR1 in normal skeletal muscle, RyR1 from animal models of heart failure is hyperphosphorylated, and the rate of calcium release and decay of calcium transients are both slowed.

Reiken et al. propose that the hyperadrenergic state of heart failure causes hyperphosphorylation of ryanodine receptors in both cardiac and skeletal muscle, allowing calcium leakage through the channels. The muscles' effort to compensate for the leakage of calcium stores may increase energy consumption, thus decreasing exercise tolerance.

Alan W. Dove

alanwdove{at}earthlink.net

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PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure

Steven Reiken, Alain Lacampagne, Hua Zhou, Aftab Kherani, Stephan E. Lehnart, Chris Ward, Fannie Huang, Marta Gaburjakova, Jana Gaburjakova, Nora Rosemblit, Michelle S. Warren, Kun-lun He, Geng-hua Yi, Jie Wang, Daniel Burkhoff, Guy Vassort, and Andrew R. Marks
J. Cell Biol. 2003 160: 919-928. [Abstract] [Full Text] [PDF]

This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dove, A. W. Search for Related Content PubMed Articles by Dove, A. W. Related Collections Related Article Social Bookmarking                      What's this?