ReviewHypertension (Dallas, Tex. : 1979)2016
Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II.
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Review in Hypertension (Dallas, Tex. : 1979), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
2.5field-weighted citation impact, top 10% of its field
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Computational Quantification of Peristalsis in Preclinical Mouse Models Using Smartphone Videography.Neurogastroenterology and motility · 2026Article
- Research progress in myocardial function and diseases related to muscarinic acetylcholine receptor (Review).International journal of molecular medicine · 2025Review
- Dual ablation of the RyR2-Ser2808 and RyR2-Ser2814 sites increases propensity for pro-arrhythmic spontaneous CaThe Journal of physiology · 2024Article
- Further investigations on the influence of protein phosphatases on the signaling of muscarinic receptors in the atria of mouse hearts.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- The Role of Muscarinic Acetylcholine Receptor MInternational journal of molecular sciences · 2024Review
- Brain Regulation of Cardiac Function during Hypoglycemia.Metabolites · 2023Review
- Impact and potential mechanism of effects of chronic moderate alcohol consumption on cardiac function in aldehyde dehydrogenase 2 gene heterozygous mice.Alcoholism, clinical and experimental research · 2022Article
- Regulation of cardiac ryanodine receptor function by the cyclic-GMP dependent protein kinase G.Current research in physiology · 2022Article
- Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.Journal of cellular and molecular medicine · 2021Article
- Acute Detubulation of Ventricular Myocytes Amplifies the Inhibitory Effect of Cholinergic Agonist on Intracellular CaFrontiers in physiology · 2021Article
- Interactive Roles of CaMKII/Ryanodine Receptor Signaling and Inflammation in Lung Diseases.Advances in experimental medicine and biology · 2021Review
- Multisite phosphorylation of the cardiac ryanodine receptor: a random or coordinated event?Pflugers Archiv : European journal of physiology · 2020Review
- Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure.ACS pharmacology & translational science · 2020Review
- Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K-AKT-nNOS signaling.The Journal of biological chemistry · 2020Article
- "A Step and a Ceiling": mechanical properties of CaPhysiological reports · 2019Article
- Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease.Scientific reports · 2019Article
- Accentuated vagal antagonism paradoxically increases ryanodine receptor calcium leak in long-term exercised Calsequestrin2 knockout mice.Heart rhythm · 2018Article
- Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure.Frontiers in physiology · 2018Review
- The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis.The Journal of general physiology · 2017Review
- Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease.Frontiers in physiology · 2017Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Hsiang-Ting HoFrom 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.).
Andriy E BelevychFrom 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.).
Bin LiuFrom 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.).
Ingrid M BonillaFrom 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.).
Przemysław B RadwańskiFrom 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.).
Igor V KubasovFrom 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.).
Héctor H ValdiviaFrom 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.).
Karsten SchoberFrom 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.).
Cynthia A CarnesFrom 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.).
Sándor GyörkeFrom 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.
Duke University · USInstitute of Evolutionary Physiology and Biochemistry · RULung Institute · US
Funding
CONTROLLED AND UNCONTROLLABLE CALCIUM RELEASE IN HEARTR01HL063043 · NHLBI · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI Sandor Gyorke · 1999 to 2026
$8.6MRyanodine Receptor Channels in Heart FailureR01HL074045 · NHLBI · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI GYORKE, SANDOR · 2003 to 2024
$8.2MReorganization of calcium signaling in heart failureR03TW005543 · FIC · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI GYORKE, SANDOR · 2001 to 2007
$235kAmerican Heart Association-American Stroke Association 16POST27540007FIC NIH HHS R03 TW005543NHLBI NIH HHS R01 HL063043NHLBI NIH HHS R01 HL074045
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.
Indexed as
AnimalsCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2Cells, CulturedCholinergic AgentsDisease Models, AnimalDogsExcitation Contraction CouplingHeart FailureMiceMyocytes, CardiacPhosphorylationReceptors, MuscarinicRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumSensitivity and SpecificityCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2Cholinergic AgentsReceptors, MuscarinicRyanodine Receptor Calcium Release ChannelCa/calmodulin-dependent protein kinase IIcalciumcarbacholheart failureprotein kinase Greactive oxygen speciesryanodine receptor calcium release channel
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