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Steven Reiken¹, Alain Lacampagne⁵, Hua Zhou⁴, Aftab Kherani⁴, Stephan E. Lehnart¹, Chris Ward⁵, Fannie Huang¹, Marta Gaburjakova¹, Jana Gaburjakova¹, Nora Rosemblit¹, Michelle S. Warren⁴, Kun-lun He², Geng-hua Yi², Jie Wang², Daniel Burkhoff², Guy Vassort⁵ and Andrew R. Marks^1,3

¹ Center for Molecular Cardiology, Department of Medicine
² Circulatory Physiology Division, Department of Medicine
³ Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032
⁴ Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032
⁵ Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France

Address correspondence to Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Room 9-401, 630 West 168th Street, New York, NY 10032. Tel.: (212) 305-0270. Fax: (212) 305-3690. E-mail: arm42{at}columbia.edu

The type 1 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 Ser²⁸⁴³ 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.

Key Words: ryanodine receptor; heart failure; skeletal muscle; excitation–contraction coupling; FKBP12

^* Abbreviations used in this paper: EC, excitation–contraction; HF, heart failure; LV, left ventricular, mAKAP, muscle A-kinase anchoring protein; P_o, open probability; PP1, protein phosphatase 1; RyR, ryanodine receptor; RyR1, type 1 RyR; SNS, sympathetic nervous system; SR, sarcoplasmic reticulum; VGCC, voltage-gated Ca²⁺ channel; WT, wild type.

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