title: Adrenergic regulation of cardiac contractility does not involve phosphorylation of the cardiac ryanodine receptor at serine 2808.
abstract: The sympathetic nervous system is a critical regulator of cardiac function (heart rate and contractility) in health and disease. Sympathetic nervous system agonists bind to adrenergic receptors that are known to activate protein kinase A, which phosphorylates target proteins and enhances cardiac performance. Recently, it has been proposed that protein kinase A-mediated phosphorylation of the cardiac ryanodine receptor (the Ca(2+) release channel of the sarcoplasmic reticulum at a single residue, Ser2808) is a critical component of sympathetic nervous system regulation of cardiac function. This is a highly controversial hypothesis that has not been confirmed by several independent laboratories. The present study used a genetically modified mouse in which Ser2808 was replaced by alanine (S2808A) to prevent phosphorylation at this site. The effects of isoproterenol (a sympathetic agonist) on ventricular performance were compared in wild-type and S2808A hearts, both in vivo and in isolated hearts. Isoproterenol effects on L-type Ca(2+) current (I(CaL)), sarcoplasmic reticulum Ca(2+) release, and excitation-contraction coupling gain were also measured. Our results showed that isoproterenol caused significant increases in cardiac function, both in vivo and in isolated hearts, and there were no differences in these contractile effects in wild-type and S2808A hearts. Isoproterenol increased I(CaL), the amplitude of the Ca(2+) transient and excitation-contraction coupling gain, but, again, there were no significant differences between wild-type and S2808A myocytes. These results show that protein kinase A phosphorylation of ryanodine receptor Ser2808 does not have a major role in sympathetic nervous system regulation of normal cardiac function.
authors.affiliation: Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: MacDonnell
authors.forename: Gerardo
authors.initials: G
authors.lastname: García-Rivas
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Scherman
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Héctor
authors.initials: H
authors.lastname: Valdivia
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D022062:Electrophysiologic Techniques, Cardiac; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism* / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol