Evidence for enhanced M3 muscarinic receptor function and sensitivity to atrial arrhythmia in the RGS2-deficient mouse

Abstract

Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic ACh receptors (M2R, M3R) are involved in vagally induced AF. M2R and M3R activate the heterotrimeric G proteins, Gi and Gq, respectively, by promoting GTP binding, and these in turn activate distinct K+ channels. Signaling is terminated by GTP hydrolysis, a process accelerated by regulator of G protein signaling (RGS) proteins. RGS2 is selective for Gq and thus may regulate atrial M3R signaling. We hypothesized that knockout of RGS2 (RGS2−/−) would render the atria more susceptible to electrically induced AF. One-month-old male RGS2−/− and C57BL/6 wild-type (WT) mice were instrumented for intracardiac electrophysiology. Atrial effective refractory periods (AERPs) were also determined in the absence and presence of carbachol, atropine, and/or the selective M3R antagonist darifenacin. Susceptibility to electrically induced AF used burst pacing and programmed electrical stimulation with one extrastimulus. Real-time RT-PCR measured atrial and ventricular content of RGS2, RGS4, M2R, M3R, and M4R mRNA. AERP was lower in RGS2−/− compared with WT mice in both the high right atrium (HRA) (30 ± 1 vs. 34 ± 1 ms, P < 0.05) and mid right atrium (MRA) (21 ± 1 vs. 24 ± 1 ms, P < 0.05). Darifenacin eliminated this difference (HRA: 37 ± 2 vs. 39 ± 2 ms, and MRA: 30 ± 2 vs. 30 ± 1, P > 0.4). RGS2−/− were more susceptible than WT mice to atrial tachycardia/fibrillation (AT/F) induction (11/22 vs. 1/25, respectively, P < 0.05). Muscarinic receptor expression did not differ between strains, whereas M2R expression was 70-fold higher than M3R ( P < 0.01). These results suggest that RGS2 is an important cholinergic regulator in the atrium and that RGS2−/− mice have enhanced susceptibility to AT/F via enhanced M3 muscarinic receptor activity.