title: Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice.
abstract: 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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Shan
authors.forename: Alexander
authors.initials: A
authors.lastname: Kushnir
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betzenhauser
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Jingdong
authors.initials: J
authors.lastname: Li
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lindegger
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D020013:Calcium Signaling; D002395:Catecholamines / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases