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

被引:193
作者
Reiken, S
Lacampagne, A
Zhou, H
Kherani, A
Lehnart, SE
Ward, C
Huang, F
Gaburjakova, M
Gaburjakova, J
Rosemblit, N
Warren, MS
He, KL
Yi, GH
Wang, J
Burkhoff, D
Vassort, G
Marks, AR
机构
[1] Columbia Univ Coll Phys & Surg, Ctr Mol Cardiol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Med, Circulatory Physiol Div, New York, NY 10032 USA
[3] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Div Cardiothorac Surg, New York, NY 10032 USA
[5] INSERM, U390, Montpellier, France
关键词
ryanodine receptor; heart failure; skeletal muscle; excitation-contraction coupling; FKBP12;
D O I
10.1083/jcb.200211012
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
T he type I ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser(2843) activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.
引用
收藏
页码:919 / 928
页数:10
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