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

Abstract

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, If; 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 IKr, 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.

Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction

“…We used a biophysically detailed model of the mouse sinus node action potential: the Hu-Zhang model. 42 In this, we incorporated the observed down-regulation of proteins responsible for the ionic currents I f , I Na , I Ca,L , I Ca,T , I K,r , I K,s , I K,ACh , I NaK , and I GJ (Hcn1, Hcn4, Scn5a, Cacna1c, Cacna1d, Cacna1h, Kcnh2, Kcnq1, Kcnj3, Kcnj5, Atp1a1, Atp1a2, Atp1a3, Cx43) (see Supplementary material online , Figure S6 ). There were no significant changes in the proteins involved in the Ca 2+ clock mechanism of pacemaking (Atp2a2, Ryr2, and Slc8a1), thus these proteins were not considered further.…”

“…To simulate initiation and conduction of pacemaker action potentials, we constructed a one-dimensional model of the sinus node and surrounding atrial muscle ( Figure 2 E ). In the sinus node segment, each node (cell) was modelled by the Hu-Zhang model 42 and in the atrial segments each node (cell) was modelled by equations from Aslanidi et al 43 In the control condition, the action potential was initiated in the centre of the sinus node and conducted to the atrial cells in both directions ( Figure 2 E ). In the HF condition, although the conduction sequence was not changed, both the pacemaker rate and the conduction of the action potential to the atrial muscle were slowed ( Figure 2 F and G ) as observed in humans with HF and in the mouse HF model.…”

Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibilty in a canine model of elite exercise

“…Since activation of I f largely occurs at voltages more negative than the maximal diastolic potential of sinus nodal cells the special importance of I f as the sinus nodal main pacemaker current has even been questioned [46, 47]. In addition, other mechanisms based on calcium handling [48,49,50] or contribution of other ion channels were proposed [51,52,53] to explain cardiac pacemaking in the sinus node. Regardless of the nature of the bradycardia, slower heart rate itself would result in longer APD and enhanced dispersion of repolarization contributing to an increased substrate for arrhythmias.…”

Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study

“…A prolonged QT interval reflects impaired cardiac repolarization that may increase tissue susceptibility to arrhythmogenesis and sudden cardiac death. Acquired LQTS is typically attributable to medications that inhibit the activity of potassium channels encoded by human Ether-à-go-go Related Gene (hERG) [5][6][7]. Congenital LQTS is linked to mutations of proteins that influence cardiac electrogenesis.…”