Absence of the Inhibitory G-Protein Gαi2 Predisposes to Ventricular Cardiac Arrhythmia

Background-We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia. Methods and Results-Mice with global genetic deletion of G alpha(i2) [G alpha(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 G alpha(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 G alpha(i1) and G alpha(i3) mice showed these abnormalities. There was no evidence for structural heart disease at this time point in the G alpha(i2) (-/-) mice as assessed by cardiac histology and echocardiography. The absence of G alpha(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 G alpha(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 G alpha(i2) (-/-) mice. There were no changes in K+ currents. Conclusions-The absence of inhibitory G-protein signaling mediated through G alpha(i2) is a substrate for ventricular arrhythmias. (Circ Arrhythm Electrophysiol. 2010; 3: 391-400.)