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Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice
Jian Shan, … , Peter J. Mohler, Andrew R. Marks
Jian Shan, … , Peter J. Mohler, Andrew R. Marks
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4388-4398. https://doi.org/10.1172/JCI32726.
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Research Article Article has an altmetric score of 9

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

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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.

Authors

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

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Figure 5

Blunted responses to Iso in RyR2-S2808A+/+ ventricular myocytes and SANCs.

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Blunted responses to Iso in RyR2-S2808A+/+ ventricular myocytes and SANC...
(A) Representative Ca2+ transients and (C) fractional shortening traces from WT and RyR2-S2808A+/+ ventricular myocytes loaded with Fura-2 paced at 3 Hz in the absence and presence of 100 nM Iso. The label "Δ 0.5” refers to a 0.5 change in the Fura-2 (340:380) ratio. (B) Summary of Ca2+ transient and (D) fractional shortening data, demonstrating that the RyR2-S2808A+/+ myocytes have blunted increases in Ca2+ transient and fractional shortening amplitude in response to Iso (*P < 0.05). (E) Representative SAPs generated from WT and RyR2-S2808A+/+ SANCs in the absence (left) and presence of 50 nM Iso (right). (F) Bar graph summarizing the rate of SAP generation in WT (n = 9) versus RyR2-S2808A+/+ SANCs (n = 8; *P < 0.05).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 9 patents
Referenced in 1 clinical guideline sources
132 readers on Mendeley
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