DREADD technology reveals major impact of Gq signaling on cardiac electrophysiology.

Aims: Signaling via Gq-coupled receptors is of profound importance in many cardiac diseases such as hypertrophy and arrhythmia. Nevertheless, owing to their widespread expression and the inability to selectively stimulate such receptors in vivo, their relevance for cardiac function is not well understood. We here use DREADD technology to understand the role of Gq-coupled signaling in vivo in cardiac function.

Methods and Results: We generated a novel transgenic mouse line that expresses a Gq-coupled DREADD (Dq) in striated muscle under the control of the MCK promotor. In vivo injection of the DREADD agonist CNO resulted in a dose-dependent, rapid mortality of the animals. In vivo ECG data revealed severe cardiac arrhythmias including lack of P-waves, AV block and ventricular tachycardia. Following Dq activation, electrophysiological malfunction of the heart could be recapitulated in the isolated heart ex vivo. Individual ventricular and atrial myocytes displayed a positive inotropic response and arrhythmogenic events in the absence of altered action potentials. Ventricular tissue sections revealed a strong co-localization of Dq with the principal cardiac connexin CX43. Western blot analysis with phosphor-specific antibodies revealed strong phosphorylation of a PKC-dependent CX43 phosphorylation site following CNO application in vivo.

Conclusions: Activation of Gq-coupled signaling has a major impact on impulse generation, impulse propagation and coordinated impulse delivery in the heart. Thus, Gq-coupled signaling does not only modulate the myocytes' Ca2+ handling but also directly alters the heart's electrophysiological properties such as intercellular communication. This study greatly advances our understanding of the plethora of modulatory influences of Gq signaling on the heart in vivo.