G_q-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation

Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gα_q/Gα₁₁-family (G_q). Besides pro-fibrotic and pro-inflammatory effects, G_q-mediated signaling induces inositol trisphosphate receptor (IP₃R)-mediated intracellular Ca²⁺ mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G_q-mediated signaling is absent.

To define the role of G_q in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gα_q/Gα₁₁-deficiency (G_q-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G_q-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G_q-KO mice-both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G_q-KO and control mice and electrically stimulated to study Ca²⁺-mobilization during excitation-contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca²⁺ waves and sarcoplasmic reticulum content-corrected Ca²⁺ sparks were less frequent in G_q-KO mice. Interestingly, nuclear but not cytosolic Ca²⁺ transient amplitudes were significantly decreased in G_q-KO mice.

G_q-signaling promotes arrhythmogenic atrial Ca²⁺-release and AF in mice. Targeting this pathway, ideally using G_q-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G_q-effector IP₃R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.