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

Steven Reiken; Alain Lacampagne; Hua Zhou; Aftab Kherani; Stephan E. Lehnart; Chris Ward; Fannie Huang; Marta Gaburjakova; Jana Gaburjakova; Nora Rosemblit; Michelle S. Warren; Kun-lun He; Geng-hua Yi; Jie Wang; Daniel Burkhoff; Guy Vassort; Andrew R. Marks

doi:10.1083/jcb.200211012

Retour

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

Article de revue

Avec comité de lecture

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

Steven Reiken, Alain Lacampagne, Hua Zhou, Aftab Kherani, Stephan E. Lehnart, Chris Ward, Fannie Huang, Marta Gaburjakova, Jana Gaburjakova, Nora Rosemblit, …

The Journal of cell biology, Vol.160(6), pp.919-928

17/03/2003

DOI: https://doi.org/10.1083/jcb.200211012

PMID: 12629052

Résumé

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.

Indicateurs

1 Consultations de la notice

Détails

Titre: PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle
Créateurs - sans rôle: Steven Reiken - Columbia University
Alain Lacampagne - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Hua Zhou - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Aftab Kherani - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Stephan E. Lehnart - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Chris Ward - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Fannie Huang - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Marta Gaburjakova - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Jana Gaburjakova - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Nora Rosemblit - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Michelle S. Warren - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Kun-lun He - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Geng-hua Yi - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Jie Wang - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Daniel Burkhoff - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Guy Vassort - Center for Molecular Cardiology, Department of Medicine Circulatory Physiology Division, Department of Medicine Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032 Cardiothoracic Surgery Division, Columbia University College of Physicians and Surgeons, New York, NY 10032 Physiopathologie Cardiovasculaire, INSERM U390, Montpellier, France
Andrew R. Marks - Columbia University
Détails de publication: The Journal of cell biology, Vol.160(6), pp.919-928
Éditeur: The Rockefeller University Press
Nombre de pages: 10
Identifiants: 99158778909311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article