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(Circulation Research. 2006;98:1422.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Bradycardia and Slowing of the Atrioventricular Conduction in Mice Lacking Ca_V3.1/_1G T-Type Calcium Channels

Matteo E. Mangoni^*, Achraf Traboulsie^*, Anne-Laure Leoni, Brigitte Couette, Laurine Marger, Khai Le Quang, Elodie Kupfer, Anne Cohen-Solal, José Vilar, Hee-Sup Shin, Denis Escande, Flavien Charpentier, Joël Nargeot, Philippe Lory

From the Institut de Génomique Fonctionnelle (M.E.M., A.T., B.C., L.M., E.K., A.C.-S., J.N., P.L.), CNRS UMR5203-INSERM U661-Université de Montpellier I–Université de Montpellier II, Département de Physiologie, Montpellier; Institut du Thorax (A.-L.L., K.L.Q., D.E., F.C.), INSERM U533, Faculté de Médecine, Nantes; Cardiovascular Research Center (J.V.), INSERM U689, Université Paris 7-Denis Diderot, Paris, France; and Center for Calcium and Learning (H.-S.S.), Korea Institute of Science and Technology, Cheongryang, Seoul, Republic of Korea.

Correspondence to Dr Matteo Mangoni, Institut de Génomique Fonctionnelle, CNRS UMR5203-INSERM U661, Université de Montpellier I–Université de Montpellier II, Département de Physiologie, 141, rue de la Cardonille, Montpellier cedex 05, F-34094 France. E-mail matteo.mangoni{at}igf.cnrs.fr

The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for Ca_v3.1/_1G T-type calcium channels (cacna1g) abolishes T-type calcium current (I_Ca,T) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca²⁺ current (I_Ca,L). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I_Ca,T was detected in right atrium myocytes in both wild-type and Ca_v3.1^–/– mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that Ca_v3.1/T-type Ca²⁺ channels contribute to SAN pacemaker activity and atrioventricular conduction.

Key Words: pacemaker activity • T-type calcium channel • sinoatrial node • conduction • knockout mice

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