Absence of the Inhibitory G-Protein Gα i2 Predisposes to Ventricular Cardiac Arrhythmia

Abstract

Background— We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia. Methods and Results— Mice with global genetic deletion of Gα i2 [Gα i2 (−/−)] were studied and found, based on telemetry, to have a prolonged QT interval on surface ECG when awake. In vivo electrophysiology studies revealed that the Gα i2 (−/−) mice have a reduced ventricular effective refractory period and a predisposition to ventricular tachycardia when challenged with programmed electrical stimulation. Neither control nor combined global deletion of Gα i1 and Gα i3 mice showed these abnormalities. There was no evidence for structural heart disease at this time point in the Gα i2 (−/−) mice as assessed by cardiac histology and echocardiography. The absence of Gα i2 thus leads to a primary electrical abnormality, and we explored the basis for this finding. With patch clamping, single isolated ventricular cells showed that Gα i2 (−/−) mice had a prolonged ventricular action potential duration (APD) but steeper action potential shortening as the diastolic interval was reduced in restitution studies. Gene expression studies showed increased expression of L-type Ca 2+ channel subunits, and patch clamping revealed an increase in these currents in Gα i2 (−/−) mice. There were no changes in K + currents. Conclusions— The absence of inhibitory G-protein signaling mediated through Gα i2 is a substrate for ventricular arrhythmias.