Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 31, Pages 19233-19244Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.666719
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Funding
- British Heart Foundation [FS/09/042/27860]
- Wellcome Trust [081475/Z/06/Z]
- National Institute for Health Research Barts Cardiovascular Biomedical Research Unit
- Fondation Coeur et Arteres
- Institut Servier
- Wellcome Trust [081475/Z/06/Z] Funding Source: Wellcome Trust
- British Heart Foundation [FS/09/042/27860] Funding Source: researchfish
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The description of potential molecular substrates for predisposition to atrial fibrillation (AF) is incomplete, and it is unknown what role regulators of G/protein signaling might play. We address whether the attenuation of RGS4 function may promote AF and the mechanism through which this occurs. For this purpose, we studied a mouse with global genetic deletion of RGS4 (RGS4(-/-)) and the normal littermate controls (RGS4(-/-)). In vivo electrophysiology using atrial burst pacing revealed that mice with global RGS4 deletion developed AF more frequently than control littermates. Isolated atrial cells from RGS4(-/-) mice show an increase in Ca2+ spark frequency under basal conditions and after the addition of endothelin-1 and abnormal spontaneous Ca2+ release events after field stimulation. Isolated left atria studied on a multielectrode array revealed modest changes in path length for re-entry but abnormal electrical events after a pacing train in RGS4(-/-) mice. RGS4 deletion results in a predisposition to atrial fibrillation from enhanced activity in the G alpha(q/11)-IP3 pathway, resulting in abnormal Ca2+ release and corresponding electrical events.
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