Absence of the Inhibitory G-protein Galphai2 Predisposes to Ventricular Cardiac Arrhythmia

Overview

Journal Circ Arrhythm Electrophysiol

Specialty Cardiology & Vascular Diseases

Date 2010 May 25

PMID 20495013

Citations 16

Authors

Zia Zuberi

Muriel Nobles

Sonia Sebastian

Alex Dyson

Shiang Y Lim

Ross Breckenridge

Lutz Birnbaumer

Andrew Tinker

Affiliations

Soon will be listed here.

Abstract

Background: We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia.

Methods And Results: Mice with global genetic deletion of Galpha(i2) [Galpha(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 Galpha(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 Galpha(i1) and Galpha(i3) mice showed these abnormalities. There was no evidence for structural heart disease at this time point in the Galpha(i2) (-/-) mice as assessed by cardiac histology and echocardiography. The absence of Galpha(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 Galpha(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 Galpha(i2) (-/-) mice. There were no changes in K(+) currents.

Conclusions: The absence of inhibitory G-protein signaling mediated through Galpha(i2) is a substrate for ventricular arrhythmias.

Citing Articles

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A modified approach for programmed electrical stimulation in mice: Inducibility of ventricular arrhythmias.

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