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

2010 | journal article. A publication with affiliation to the University of Göttingen.

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​Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice​
Shan, J.; Kushnir, A.; Betzenhauser, M. J.; Reiken, S.; Li, J.; Lindegger, N. & Mongillo, M. et al.​ (2010) 
Journal of Clinical Investigation120(12) pp. 4388​-4398​.​ DOI: 

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Shan, Jian; Kushnir, Alexander; Betzenhauser, Matthew J.; Reiken, Steven; Li, Jingdong; Lindegger, Nicolas; Mongillo, Marco; Mohler, Peter J.; Marks, Andrew R.; Lehnart, Stephan E. 
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.
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Journal of Clinical Investigation 
0021-9738; 1558-8238



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