Muscarinic type-1 receptors contribute to I in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.

Background: Basal and acetylcholine-gated inward-rectifier K-currents (I and I, respectively) are altered in atrial fibrillation (AF). G-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating I. Although a role for G-coupled non-M-receptor subtypes has been suggested, the precise regulation of I by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M-receptor-mediated I regulation and its remodeling in chronic AF (cAF).

Methods And Results: M-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, whereas M-receptor levels were unchanged. The regulation of I by M-receptors was investigated in right-atrial cardiomyocytes using two applications of the M-receptor agonist carbachol (CCh, 2μM), with pharmacological interventions during the second application. CCh application produced a rapid current increase (Peak-I), which declined to a quasi-steady-state level (Qss-I). In sinus rhythm (Ctl) the selective M-receptor antagonists pirenzepine (10nM) and muscarinic toxin-7 (MT-7, 10nM) significantly inhibited CCh-activated Peak-I, whereas in cAF they significantly reduced both Peak- and Qss-I, with no effects on basal inward-rectifier currents in either group. Conversely, the selective M-receptor agonist McN-A-343 (100μM) induced a current similar to the CCh-activated current in Ctl atrial cardiomyocytes pretreated with pertussis toxin to inhibit M-receptor-mediated G-protein signaling, which was abolished by MT-7. Computational modeling indicated that M- and M-receptors redundantly activate I to abbreviate APD, albeit with predominant effects of M-receptors.

Conclusion: Our data suggest that G-coupled M-receptors also regulate human atrial I and that their relative contribution to I activation is increased in cAF patients. We provide novel insights about the role of non-M-receptors in human atrial cardiomyocytes, which may have important implications for understanding AF pathophysiology.