This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 98/11/1422    most recent 01.RES.0000225862.14314.49v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mangoni, M. E. Articles by Lory, P. Search for Related Content PubMed PubMed Citation Articles by Mangoni, M. E. Articles by Lory, P. Related Collections Electrophysiology Pacemaker Genetically altered mice Ion channels/membrane transport

(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

This article has been cited by other articles:

				G. Barbara, A. Alloui, J. Nargeot, P. Lory, A. Eschalier, E. Bourinet, and J. Chemin T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids J. Neurosci., October 21, 2009; 29(42): 13106 - 13114. [Abstract] [Full Text] [PDF]

				N. J. Chandler, I. D. Greener, J. O. Tellez, S. Inada, H. Musa, P. Molenaar, D. DiFrancesco, M. Baruscotti, R. Longhi, R. H. Anderson, et al. Molecular Architecture of the Human Sinus Node: Insights Into the Function of the Cardiac Pacemaker Circulation, March 31, 2009; 119(12): 1562 - 1575. [Abstract] [Full Text] [PDF]

				S. R. Houser Ca2+ Signaling Domains Responsible For Cardiac Hypertrophy and Arrhythmias Circ. Res., February 27, 2009; 104(4): 413 - 415. [Full Text] [PDF]

				C.-S. Chiang, C.-H. Huang, H. Chieng, Y.-T. Chang, D. Chang, J.-J. Chen, Y.-C. Chen, Y.-H. Chen, H.-S. Shin, K. P. Campbell, et al. The CaV3.2 T-Type Ca2+ Channel Is Required for Pressure Overload-Induced Cardiac Hypertrophy in Mice Circ. Res., February 27, 2009; 104(4): 522 - 530. [Abstract] [Full Text] [PDF]

				O. Ramadan, Y. Qu, R. Wadgaonkar, G. Baroudi, E. Karnabi, M. Chahine, and M. Boutjdir Phosphorylation of the Consensus Sites of Protein Kinase A on {alpha}1D L-type Calcium Channel J. Biol. Chem., February 20, 2009; 284(8): 5042 - 5049. [Abstract] [Full Text] [PDF]

				W. L. Ernst, Y. Zhang, J. W. Yoo, S. J. Ernst, and J. L. Noebels Genetic Enhancement of Thalamocortical Network Activity by Elevating {alpha}1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy J. Neurosci., February 11, 2009; 29(6): 1615 - 1625. [Abstract] [Full Text] [PDF]

				F. Marni, Y. Wang, M. Morishima, T. Shimaoka, T. Uchino, M. Zheng, T. Kaku, and K. Ono 17{beta}-Estradiol Modulates Expression of Low-Voltage-Activated CaV3.2 T-Type Calcium Channel via Extracellularly Regulated Kinase Pathway in Cardiomyocytes Endocrinology, February 1, 2009; 150(2): 879 - 888. [Abstract] [Full Text] [PDF]

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				K. Fukuzaki, T. Sato, T. Miki, S. Seino, and H. Nakaya Role of sarcolemmal ATP-sensitive K+ channels in the regulation of sinoatrial node automaticity: an evaluation using Kir6.2-deficient mice J. Physiol., June 1, 2008; 586(11): 2767 - 2778. [Abstract] [Full Text] [PDF]

				Q. Zhang, V. Timofeyev, L. Lu, N. Li, A. Singapuri, M. K. Long, C. T. Bond, J. P. Adelman, and N. Chiamvimonvat Functional Roles of a Ca2+-Activated K+ Channel in Atrioventricular Nodes Circ. Res., February 29, 2008; 102(4): 465 - 471. [Abstract] [Full Text] [PDF]

				J. Thireau, B. L. Zhang, D. Poisson, and D. Babuty Heart rate variability in mice: a theoretical and practical guide Exp Physiol, January 1, 2008; 93(1): 83 - 94. [Abstract] [Full Text] [PDF]

				J. Chemin, A. Mezghrani, I. Bidaud, S. Dupasquier, F. Marger, C. Barrere, J. Nargeot, and P. Lory Temperature-dependent Modulation of CaV3 T-type Calcium Channels by Protein Kinases C and A in Mammalian Cells J. Biol. Chem., November 9, 2007; 282(45): 32710 - 32718. [Abstract] [Full Text] [PDF]

				M. Baruscotti and R. B. Robinson Electrophysiology and pacemaker function of the developing sinoatrial node Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2613 - H2623. [Abstract] [Full Text] [PDF]

				M. F. Navedo, G. C. Amberg, R. E. Westenbroek, M. J. Sinnegger-Brauns, W. A. Catterall, J. Striessnig, and L. F. Santana Cav1.3 channels produce persistent calcium sparklets, but Cav1.2 channels are responsible for sparklets in mouse arterial smooth muscle Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1359 - H1370. [Abstract] [Full Text] [PDF]

				W. M.H. Hoogaars, A. Engel, J. F. Brons, A. O. Verkerk, F. J. de Lange, L.Y. E. Wong, M. L. Bakker, D. E. Clout, V. Wakker, P. Barnett, et al. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria Genes & Dev., May 1, 2007; 21(9): 1098 - 1112. [Abstract] [Full Text] [PDF]

				H. Dobrzynski, M. R. Boyett, and R. H. Anderson New Insights Into Pacemaker Activity: Promoting Understanding of Sick Sinus Syndrome Circulation, April 10, 2007; 115(14): 1921 - 1932. [Full Text] [PDF]

				J. Chemin, J. Nargeot, and P. Lory Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels J. Biol. Chem., January 26, 2007; 282(4): 2314 - 2323. [Abstract] [Full Text] [PDF]

				A. Traboulsie, J. Chemin, M. Chevalier, J.-F. Quignard, J. Nargeot, and P. Lory Subunit-specific modulation of T-type calcium channels by zinc J. Physiol., January 1, 2007; 578(1): 159 - 171. [Abstract] [Full Text] [PDF]