Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice

Jian Shan, Alexander Kushnir, Matthew J. Betzenhauser, Steven Reiken, Jingdong Li, Stephan E. Lehnart, Nicolas Lindegger, Marco Mongillo, Peter J. Mohler, Andrew R. Marks

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

During the classic "fight-or-flight" stress response, sympathetic nervous system activation leads to catecholamine release, which increases heart rate and contractility, resulting in enhanced cardiac output. Catecholamines bind to β-adrenergic receptors, causing cAMP generation and activation of PKA, which phosphorylates multiple targets in cardiac muscle, including the cardiac ryanodine receptor/calcium release channel (RyR2) required for muscle contraction. PKA phosphorylation of RyR2 enhances channel activity by sensitizing the channel to cytosolic calcium (Ca2+). Here, we found that mice harboring RyR2 channels that cannot be PKA phosphorylated (referred to herein as RyR2-S2808A+/+ mice) exhibited blunted heart rate and cardiac contractile responses to catecholamines (isoproterenol). The isoproterenol-induced enhancement of ventricular myocyte Ca2+ transients and fractional shortening (contraction) and the spontaneous beating rate of sinoatrial nodal cells were all blunted in RyR2-S2808A+/+ mice. The blunted cardiac response to catecholamines in RyR2-S2808A +/+ mice resulted in impaired exercise capacity. RyR2-S2808A +/+ mice were protected against chronic catecholaminergic-induced cardiac dysfunction. These studies identify what we believe to be new roles for PKA phosphorylation of RyR2 in both the heart rate and contractile responses to acute catecholaminergic stimulation.

Original languageEnglish (US)
Pages (from-to)4388-4398
Number of pages11
JournalJournal of Clinical Investigation
Volume120
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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