title: Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II.
abstract: Although the effects and the underlying mechanism of sympathetic stimulation on cardiac Ca handling are relatively well established both in health and disease, the modes of action and mechanisms of parasympathetic modulation are poorly defined. Here, we demonstrate that parasympathetic stimulation initiates a novel mode of excitation-contraction coupling that enhances the efficiency of cardiac sarcoplasmic reticulum Ca store utilization. This efficient mode of excitation-contraction coupling involves reciprocal changes in the phosphorylation of ryanodine receptor 2 at Ser-2808 and Ser-2814. Specifically, Ser-2808 phosphorylation was mediated by muscarinic receptor subtype 2 and activation of PKG (protein kinase G), whereas dephosphorylation of Ser-2814 involved activation of muscarinic receptor subtype 3 and decreased reactive oxygen species-dependent activation of CaMKII (Ca/calmodulin-dependent protein kinase II). The overall effect of these changes in phosphorylation of ryanodine receptor 2 is an increase in systolic Ca release at the low sarcoplasmic reticulum Ca content and a paradoxical reduction in aberrant Ca leak. Accordingly, cholinergic stimulation of cardiomyocytes isolated from failing hearts improved Ca cycling efficiency by restoring altered ryanodine receptor 2 phosphorylation balance.
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bonilla
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Przemysław B
authors.initials: PB
authors.lastname: Radwański
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kubasov
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Karsten
authors.initials: K
authors.lastname: Schober
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.).
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.affiliation: From the Department of Physiology and Cell Biology (H.-T.H., A.E.B., B.L., P.B.R., S.G.), College of Pharmacy (I.M.B., P.B.R., C.A.C.), and College of Veterinary Medicine (K.S.), The Ohio State University, Columbus; Davis Heart and Lung Research Institute, Columbus, OH (H.-T.H., A.E.B., B.L., I.M.B., P.B.R., C.A.C., S.G.); Department of Medicine, Duke University, Durham, NC (H.-T.H.); Laboratory of Neuromuscular Physiology, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Petersburg, Russia (I.V.K.); and Center for Arrhythmia Research, Cardiovascular Division of the Department of Internal Medicine, University of Michigan, Ann Arbor (H.H.V.). sandor.gyorke@osumc.edu.
authors.forename: Sándor
authors.initials: S
authors.lastname: Györke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D056966:Excitation Contraction Coupling / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D018678:Cholinergic Agents; D011976:Receptors, Muscarinic; D019837:Ryanodine Receptor Calcium Release Channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Ca/calmodulin-dependent protein kinase II; calcium; carbachol; heart failure; protein kinase G; reactive oxygen species; ryanodine receptor calcium release channel