| First Author | Shan J | Year | 2010 |
| Journal | J Clin Invest | Volume | 120 |
| Issue | 12 | Pages | 4388-98 |
| PubMed ID | 21099118 | Mgi Jnum | J:171860 |
| Mgi Id | MGI:5000199 | Doi | 10.1172/JCI32726 |
| Citation | Shan J, et al. (2010) Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest 120(12):4388-98 |
| abstractText | 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 beta-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 (Ca(2)+). 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 Ca(2)+ 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. |
