ArticleCardiovascular research2015
Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII.
Article in Cardiovascular research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis.Frontiers in cardiovascular medicine · 2021Pooled it
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- Blebbistatin reduces calcium buffering in cardiomyocytes: Consequences for cellular electrophysiology.The Journal of physiology · 2026Article
- Atrial Fibrillation Increases Proarrhythmic Mechanisms in the Ventricle.JACC. Basic to translational science · 2026Article
- Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models.Signal transduction and targeted therapy · 2026Article
- Felcisetrag stimulates 5-HTNaunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Conventional Antiarrhythmics Class I-IV, Late INa Inhibitors, IKs Enhancers, RyR2 Stabilizers, Gap Junction Modulators, Atrial-Selective Antiarrhythmics, and Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Therapy in Arrhythmias.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Synergistic antiarrhythmic mechanism of IJournal of translational medicine · 2025Article
- Energy metabolism in cardiovascular diseases: unlocking the hidden powerhouse of cardiac pathophysiology.Frontiers in endocrinology · 2025Review
- Enhanced Late IInternational journal of molecular sciences · 2024Article
- Calcium-mediated DAD in membrane potentials and triggered activity in atrial myocytes of ETV1Journal of cellular and molecular medicine · 2024Article
- Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.Cardiovascular research · 2024Article
- NaInternational journal of molecular sciences · 2024Article
- The inotropic and arrhythmogenic effects of acutely increased late IFrontiers in cardiovascular medicine · 2024Article
- CaMK II in Cardiovascular Diseases, Especially CaMK II-δ: Friends or Enemies.Drug design, development and therapy · 2024Review
- Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis.Cardiovascular research · 2023Article
- NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.Antioxidants (Basel, Switzerland) · 2023Review
- Decreased FAM13B Expression Increases Atrial Fibrillation Susceptibility by Regulating Sodium Current and Calcium Handling.JACC. Basic to translational science · 2023Article
- Molecular and Functional Relevance of NaInternational journal of molecular sciences · 2023Article
- A deep learning platform to assess drug proarrhythmia risk.Cell stem cell · 2023Article
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsEnhanced cardiac late Na current (late INa) and increased sarcoplasmic reticulum (SR)-Ca(2+)-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late INa and SR-Ca(2+)-leak in atrial cardiomyocytes (CMs). METHODS AND
resultsIn murine atrial CMs, SR-Ca(2+)-leak was increased by the late INa enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca(2+)/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late INa (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca(2+)-leak. The SR-Ca(2+)-leak induction by ATX-II was not detected when either the Na(+)/Ca(2+) exchanger was inhibited (KBR) or in CaMKIIδc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late INa-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late INa did not alter Ca(2+)-transient amplitude or SR-Ca(2+)-load. However, upon late INa activation and simultaneous CaMKII inhibition, Ca(2+)-transient amplitude and SR-Ca(2+)-load were increased, whereas PKA inhibition reduced Ca(2+)-transient amplitude and load and additionally slowed Ca(2+) elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late INa, CaMKII, or PKA reduced the SR-Ca(2+)-leak.
conclusionLate INa exerts distinct effects on Ca(2+) homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late INa represents a potential approach to attenuate CaMKII activation and decreases SR-Ca(2+)-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late INa inhibition.
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