ArticleAmerican journal of physiology. Heart and circulatory physiology2016
CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases.
Article in American journal of physiology. Heart and circulatory physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- cAMP-Activated EPAC Signaling Is an Integral Component of Cardiac Pacemaker Cell Automaticity.Circulation. Arrhythmia and electrophysiology · 2026Article
- Emerging Regulatory Mechanisms in Sinoatrial Node Automaticity.Journal of cellular and molecular medicine · 2026Review
- Heliox preconditioning exerts pulmonary protection effects on neonatal acute respiratory distress syndrome by inhibiting oxidative stress and apoptosis.Frontiers in pharmacology · 2025Article
- CaCells · 2024Review
- Pacemaker Channels and the Chronotropic Response in Health and Disease.Circulation research · 2024Review
- Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.The Journal of general physiology · 2022Article
- Article
- Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond.International journal of molecular sciences · 2021Review
- Chronic CaThe Journal of pharmacology and experimental therapeutics · 2021Article
- Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome.Journal of cardiovascular development and disease · 2021Review
- SOCE in the cardiomyocyte: the secret is in the chambers.Pflugers Archiv : European journal of physiology · 2021Review
- Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity.Frontiers in cardiovascular medicine · 2021Article
- IPAmerican journal of physiology. Heart and circulatory physiology · 2021Article
- Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function.Frontiers in physiology · 2021Review
- Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species viaCirculation research · 2020Article
- The Cardiac Pacemaker Story-Fundamental Role of the NaFrontiers in pharmacology · 2020Review
- Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans.Frontiers in physiology · 2020Review
- SOCE and STIM1 signaling in the heart: Timing and location matter.Cell calcium · 2019Review
- Unique CaInternational journal of molecular sciences · 2018Review
- [Inhibition of CaMKII alleviates myocardial ischemia?reperfusion injury by reducing mitochondrial oxidative stress in isolated perfused rat heart].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2018Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca(2+) releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na(+)/Ca(2+)exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKII-dependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr(17) site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKII-dependent Ser(2815) site was ∼10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca(2+) transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKII-dependent phosphorylation (indexed by PLB phosphorylation at the Thr(17)site) produced by CaMKII inhibition, β-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca(2+) replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths (R(2) = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca(2+) cycling proteins PLB, RyR, L-type Ca(2+) channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve cardiac pacemaker function.
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