β-adrenergic regulation of late Na+ current during cardiac action potential is mediated by both PKA and CaMKII

Journal of Molecular and Cellular Cardiology
Bence HegyiLeighton T Izu

Abstract

Late Na+ current (INaL) significantly contributes to shaping cardiac action potentials (APs) and increased INaL is associated with cardiac arrhythmias. β-adrenergic receptor (βAR) stimulation and its downstream signaling via protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways are known to regulate INaL. However, it remains unclear how each of these pathways regulates INaL during the AP under physiological conditions. Here we performed AP-clamp experiments in rabbit ventricular myocytes to delineate the impact of each signaling pathway on INaL at different AP phases to understand the arrhythmogenic potential. During the physiological AP (2 Hz, 37 °C) we found that INaL had a basal level current independent of PKA, but partially dependent on CaMKII. βAR activation (10 nM isoproterenol, ISO) further enhanced INaL via both PKA and CaMKII pathways. However, PKA predominantly increased INaL early during the AP plateau, whereas CaMKII mainly increased INaL later in the plateau and during rapid repolarization. We also tested the role of key signaling pathways through exchange protein activated by cAMP (Epac), nitric oxide synthase (NOS) and reactive oxygen species (ROS). Direct Epac stimulation enha...Continue Reading

Citations

Mar 1, 2019·Circulation Research·Céline Marionneau, Hugues Abriel
May 16, 2019·Canadian Journal of Physiology and Pharmacology·Bence HegyiTamás Bányász
Sep 10, 2020·Annals of the New York Academy of Sciences·Khalil SaadehKamalan Jeevaratnam
May 7, 2020·Frontiers in Pharmacology·Balázs HorváthTamás Bányász
Oct 10, 2020·American Journal of Physiology. Heart and Circulatory Physiology·M TrumS Wagner
Dec 2, 2020·Channels·Kornél KistamásPéter P Nánási
Nov 26, 2020·Basic Research in Cardiology·Bence HegyiDonald M Bers
Nov 20, 2020·Pflügers Archiv : European journal of physiology·Abdulaziz A AlzahraniAndrew P Holmes
Mar 16, 2021·Free Radical Biology & Medicine·Diana Bou-TeenMarisol Ruiz-Meana
Dec 30, 2020·Journal of Molecular and Cellular Cardiology·Madison B NowakSeth H Weinberg
May 1, 2021·Circulation Research·Bence HegyiDonald M Bers
Jun 6, 2021·Journal of Molecular and Cellular Cardiology·Balázs HorváthPéter P Nánási

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