The G-protein–gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation

Abstract

Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein–activated K+ current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4−/− mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4−/− mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4−/− animals. Although the relative extent of heart rate regulation of Girk4−/− mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4−/− animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.

G protein-gated I KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

“…The muscarinic-gated K + channel (I KACh ) is involved in the negative chronotropic effect of the parasympathetic nervous system on heart rate (20,21). Two subunits of the G-protein activated inwardly rectifying K + channels (GIRK1 and GIRK4) of the GIRK/ Kir3 subfamily assemble as heterotetramers to form cardiac I KACh channels (22).…”

“…Two subunits of the G-protein activated inwardly rectifying K + channels (GIRK1 and GIRK4) of the GIRK/ Kir3 subfamily assemble as heterotetramers to form cardiac I KACh channels (22). Indeed, both Girk1 −/− and Girk4 −/− mice lack cardiac I KACh (20,21,23). We recently showed that silencing of the hyperpolarization-activated current "funny" (I f ) channel in mice induces a complex arrhythmic profile that can be rescued by concurrent genetic ablation of Girk4 (24).…”

Cardiac ion channels

“…73 In the SA node, I KACh is responsible for vagal control of heart rate. 74 In atrial myocytes, I KACh contributes to repolarization and channel activation decreases action potential duration. I KACh inhibition prolongs the atrial refractory period without affecting the ventricles, making it an attractive target for drugs designed to treat AF.…”

“…Mice with genetic ablation of Kir3.1 or Kir3.4 are viable and lack any I KACh current. 78,74 Mice from both strains have normal resting heart rates, but significantly diminished vagal control of heart rate. Mice deficient in Kir3.4 were shown to be resistant to experimentally-induced AF.…”

Potassium channels in the sinoatrial node and their role in heart rate control

“…GIRK channels are also important in the recovery of heart rate: GIRK4 knockout mice when exercised show a delay in the time taken to return to the resting heart rate [54]. This is intriguing as a delayed recovery of heart rate with exercise is associated with poor outcomes [55].…”