Absence of the Inhibitory G-Protein Gα _i2 Predisposes to Ventricular Cardiac Arrhythmia

Abstract

Background We have explored the role that inhibitory heterotrimeric G-proteins have in ventricular arrhythmia. Methods and Results We studied mice with global genetic deletion of Gαi2 (Gαi2 (−/−)) and find that they have a prolonged QT interval on the surface ECG when awake and studied with telemetry. We used in-vivo electrophysiology studies and found that the Gαi2 (−/−) mice have a reduced ventricular effective refractory period and a predisposition to ventricular tachycardia when challenged with programmed electrical stimulation. Neither control nor mice with combined global deletion of Gαi1 and Gαi3 showed these abnormalities. There was no evidence for structural heart disease at this time point in the Gαi2 (−/−) mice as assessed by cardiac histology and echocardiography. The absence of Gαi2 thus leads to a primary electrical abnormality and we explored the basis for this. Single isolated ventricular cells studied using patch clamping showed that Gαi2 (−/−) mice had a prolonged ventricular action potential duration but steeper action potential shortening as the diastolic interval was reduced in restitution studies. Gene expression studies showed increased expression of L-type Ca2+ channel subunits and patch clamping revealed an increase in these currents in Gαi2 (−/−) mice. There were no changes in K+ currents. Conclusion Thus the absence of inhibitory G-protein signaling in particular that mediated via Gαi2 is a substrate for ventricular arrhythmias.

Gαi2- and Gαi3-Specific Regulation of Voltage-Dependent L-Type Calcium Channels in Cardiomyocytes

“…Although the issue has also been addressed by others [19], [20], [33], our study is the first to demonstrate small but significant changes of basal whole-cell current density: a reduction in myocytes from Gα i2 −/− mice and an increase in myocytes from Gα i3 −/− mice. The altered steady-state inactivation and recovery observed with Gα i2 −/− under basal conditions (Fig.…”

“…This likely translates into the more reduced peak in the current voltage plot in our study. Interestingly, Zuberi et al [19] compared Gα i2 −/− mice with Gα i1 −/− /Gα i3 −/− double knockout mice and found distinct effects on surface ECGs: in Gα i2 −/− animals (but not in the double knockout mice), the effective refractory period was reduced and ventricular arrhythmias were induced more easily. In summary, Gα i2 protein deletion showed dramatic consequences on channel regulation in vivo and ex vivo .…”

Essential Role of the m2R-RGS6-IKACh Pathway in Controlling Intrinsic Heart Rate Variability

“…In vivo electrophysiological studies using the EPR-800 catheter were carried out as previously described [18]. Atrial burst pacing was found to be the most consistent method for AF induction, and was performed at a rate of 600 bpm (100 ms coupling interval) for 25 s after which pacing was switched off.…”

The role of GαO‐mediated signaling in the rostral ventrolateral medulla oblongata in cardiovascular reflexes and control of cardiac ventricular excitability

“…Our own previous studies showed an effect on cardiac function in global G α i2 KO mice, though we have ascribed this largely to direct effects on cardiac tissue (Zuberi et al. , ). Other investigators have shown a potential role for G α i2 in the rat in mediating hypertensive responses (Wainford et al.…”

“…An octapolar 1.1F cardiac electrophysiology catheter was inserted into the right ventricular apex through the right internal jugular vein to pace the heart as previously described (Zuberi et al. ; Machhada et al. ).…”