title: Absence of the Regulator of G-protein Signaling, RGS4, Predisposes to Atrial Fibrillation and Is Associated with Abnormal Calcium Handling.
abstract: 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 Ca(2+) spark frequency under basal conditions and after the addition of endothelin-1 and abnormal spontaneous Ca(2+) 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 Gαq/11-IP3 pathway, resulting in abnormal Ca(2+) release and corresponding electrical events.
authors.affiliation: From the British Heart Foundation Laboratories, Department of Medicine, University College London, Rayne Institute, London WC1E 6JJ, United Kingdom and the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: Aaisha
authors.initials: A
authors.lastname: Opel
authors.affiliation: the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: Muriel
authors.initials: M
authors.lastname: Nobles
authors.affiliation: the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.affiliation: the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Finlay
authors.affiliation: the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: Naomi
authors.initials: N
authors.lastname: Anderson
authors.affiliation: From the British Heart Foundation Laboratories, Department of Medicine, University College London, Rayne Institute, London WC1E 6JJ, United Kingdom and.
authors.forename: Ross
authors.initials: R
authors.lastname: Breckenridge
authors.affiliation: From the British Heart Foundation Laboratories, Department of Medicine, University College London, Rayne Institute, London WC1E 6JJ, United Kingdom and the William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom a.tinker@qmul.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004558:Electric Stimulation; D020022:Genetic Predisposition to Disease; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020710:RGS Proteins; C098799:RGS4 protein; D002118:Calcium
keywords: arrhythmia; atrial fibrillation; calcium; cardiac muscle; cell signaling; electrophysiology; inositol 1,4,5-trisphosphate (IP3); regulator of G protein signaling (RGS)