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Am J Physiol Heart Circ Physiol 286: H2065-H2071, 2004. First published January 22, 2004; doi:10.1152/ajpheart.00933.2003
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Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes

Ana M. Gómez,1 Benoît-Gilles Kerfant,1 Guy Vassort,1 and Achilles J. Pappano2

1Physiopathologie Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale U-637, EA-3759, Centre Hospitalier Universitaire Arnaud de Villeneuve, F-34295 Montpellier, France; and 2Pharmacology, University of Connecticut Health Center, Farmington, Connecticut 06030

Submitted 2 October 2003 ; accepted in final form 16 January 2004

We recently showed that colchicine treatment of rat ventricular myocytes increases the L-type Ca2+ current (ICa) and intracellular Ca2+ concentration ([Ca2+]i) transients and interferes with adrenergic signaling. These actions were ascribed to adenylyl cyclase (AC) stimulation after Gs activation by {alpha},{beta}-tubulin. Colchicine depolymerizes microtubules into {alpha},{beta}-tubulin dimers. This study analyzed muscarinic signals in myocytes with intact or depolymerized microtubules. Myocytes were loaded with the Ca2+ indicator fluo 3 and were field stimulated at 1 Hz or voltage clamped. In untreated cells, carbachol (CCh; 1 µM) induced ACh-activated K+ current [IK(ACh)], which happens via {beta}{gamma}-subunits from the activation of Gi. Carbachol also reduced [Ca2+]i transients and contractions. Once Gi is activated by muscarinic agonist, the {alpha}i-subunit is released from the {beta}{gamma}-subunits, but it is silent, and its inhibition of the AC/cAMP cascade, manifested by ICa reduction, is not seen unless AC has been previously activated. In colchicine-treated cells, CCh caused greater reductions of [Ca2+]i transients and contractions than in untreated cells. The {alpha}i-subunit became effective in signaling through the AC/cAMP cascade and reduced ICa without changing its voltage-dependence. Isoproterenol (Iso) regained its efficacy and reversed ICa inhibition by CCh. Stimulation of ICa by forskolin persisted in colchicine-treated cells when Iso was ineffective. The effect of CCh on IK(ACh) was occluded in colchicine-treated cells. Colchicine treatment, per se, may increase IK(ACh) by {beta}{gamma}-subunits released from Gs to mask this effect of CCh. Microtubules suppress ICa regulation by {alpha}i; their disruption releases restraints that unmask muscarinic inhibition of ICa. Summarily, colchicine treatment reverses regulation of ventricular excitation-contraction coupling by autonomic agents.

cytoskeleton; excitation-contraction coupling; colchicine


Address for reprint requests and other correspondence: A. M. Gómez, Physiopathologie Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale U-637, Centre Hospitalier Universitaire Arnaud de Villeneuve, F-34295 Montpellier, France (E-mail: agomez{at}montp.inserm.fr).




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