Contribution of the Kir3.1 Subunit to the Muscarinic-gated Atrial Potassium Channel IKACh

Abstract

The muscarinic-gated atrial potassium (I KACh ) channel contributes to the heart rate decrease triggered by the parasympathetic nervous system. I KACh is a heteromultimeric complex formed by Kir3.1 and Kir3.4 subunits, although Kir3.4 homomultimers have also been proposed to contribute to this conductance. While Kir3.4 homomultimers evince many properties of I KACh , the contribution of Kir3.1 to I KACh is less well understood. Here, we explored the significance of Kir3.1 using knock-out mice. Kir3.1 knock-out mice were viable and appeared normal. The loss of Kir3.1 did not affect the level of atrial Kir3.4 protein but was correlated with a loss of carbachol-induced current in atrial myocytes. Low level channel activity resembling recombinant Kir3.4 homomultimers was observed in 40% of the cellattached patches from Kir3.1 knock-out myocytes. Channel activity typically ran down quickly, however, and was not recovered in the inside-out configuration despite the addition of GTP and ATP to the bath. Both Kir3.1 knock-out and Kir3.4 knock-out mice exhibited mild resting tachycardias and blunted responses to pharmacological manipulation intended to activate I KACh . We conclude that Kir3.1 confers properties to I KACh that enhance channel activity and that Kir3.4 homomultimers do not contribute significantly to the muscarinic-gated potassium current.

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

“…As was shown previously (21,23), the heart rate of Girk4 −/− mice was significantly higher than the heart rate of WT controls, and these mice presented normal AV conduction and response to injection of atropine and propranolol (Fig. 1D).…”

“…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).…”

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

“…GIRK1 or GIRK4 knockout mice exhibit slightly elevated resting heart rates (Bettahi et al, 2002). Atomoxetine and reboxetine are associated with modest increases in heart rate (Hajós et al, 2004;Simpson and Plosker, 2004) and tachycardia in cases of toxicity (LoVecchio and Kashani, 2006).…”

Spinal G-Protein-Gated K+Channels Formed by GIRK1 and GIRK2 Subunits Modulate Thermal Nociception and Contribute to Morphine Analgesia

“…Mice were housed in a temperaturecontrolled room on a 12 hr light/dark cycle, with food and water available ad libitum. The generation of GIRK1 knock-out (Bettahi et al, 2002), GIRK2 knock-out (Signorini et al, 1997), GIRK3 knock-out (Torrecilla et al, 2002), and GIRK2/GIRK3 double knock-out (Torrecilla et al, 2002) mice was described previously. The GIRK null mutations were backcrossed through at least nine rounds against the C57BL/6 mouse strain before initiating this study.…”