Absence of the inhibitory G-protein Galphai2 predisposes to ventricular cardiac arrhythmia.
BACKGROUND
We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia.


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.
Zuberi
Zia
Z
Department of Medicine and Hatter Cardiovascular Institute, University College London, 5 University Street, London, England, UK.
Nobles
Muriel
M
Sebastian
Sonia
S
Dyson
Alex
A
Lim
Shiang Y
SY
Breckenridge
Ross
R
Birnbaumer
Lutz
L
Tinker
Andrew
A
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D018619:Echocardiography, Doppler, Pulsed; D015716:Electrocardiography, Ambulatory; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency* / Q000235:genetics; D006329:Heart Conduction System / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013686:Telemetry; D013997:Time Factors
D020746:Calcium Channels, L-Type; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse; D011188:Potassium; D002118:Calcium