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Absence of the inhibitory G-protein Galphai2 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 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.

SUBMITTER: Zuberi Z

PROVIDER: S-EPMC3401367 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Absence of the inhibitory G-protein Galphai2 predisposes to ventricular cardiac arrhythmia.

Zuberi Zia Z Nobles Muriel M Sebastian Sonia S Dyson Alex A Lim Shiang Y SY Breckenridge Ross R Birnbaumer Lutz L Tinker Andrew A

Circulation. Arrhythmia and electrophysiology 20100521 4

<h4>Background</h4>We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia.<h4>Methods and results</h4>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 challen ...[more]

PMID: 20495013

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Project description:KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

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Absence of the inhibitory G-protein Galphai2 predisposes to ventricular cardiac arrhythmia.

Publications

Absence of the inhibitory G-protein Galphai2 predisposes to ventricular cardiac arrhythmia.

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