Physiological Roles of the Rapidly Activated Delayed Rectifier K⁺ Current in Adult Mouse Heart Primary Pacemaker Activity

• Main Authors: Wei Hu, Robert B. Clark, Wayne R. Giles, Erwin Shibata, Henggui Zhang
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: mouse heart; sino-atrial node; SAN; mathematical modeling; spontaneous pacemaker activity; repolarization
• Online Access: https://www.mdpi.com/1422-0067/22/9/4761
• ISSN: 1661-6596; 1422-0067

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na⁺, K⁺ and Ca²⁺ that produce SAN action potentials (AP) and ‘pacemaker depolarizations’ in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca²⁺-regulated mechanism based on a requirement for phasic release of Ca²⁺ from intracellular stores and activation of an inward current-mediated by Na⁺/Ca²⁺ exchange; (ii) time- and voltage-dependent activation of Na⁺ or Ca²⁺ currents, as well as a cyclic nucleotide-activated current, I_f; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K⁺ current, often denoted I_Kr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K⁺ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K⁺ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K⁺ current can contribute to its role in generating spontaneous myogenic activity.