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Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes

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 (I_Ca) and intracellular Ca²⁺ concentration ([Ca²⁺]_i) transients and interferes with adrenergic signaling. These actions were ascribed to adenylyl cyclase (AC) stimulation after G_s activation by ,-tubulin. Colchicine depolymerizes microtubules into ,-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 [I_K(ACh)], which happens via -subunits from the activation of G_i. Carbachol also reduced [Ca²⁺]_i transients and contractions. Once G_i is activated by muscarinic agonist, the _i-subunit is released from the -subunits, but it is silent, and its inhibition of the AC/cAMP cascade, manifested by I_Ca 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 _i-subunit became effective in signaling through the AC/cAMP cascade and reduced I_Ca without changing its voltage-dependence. Isoproterenol (Iso) regained its efficacy and reversed I_Ca inhibition by CCh. Stimulation of I_Ca by forskolin persisted in colchicine-treated cells when Iso was ineffective. The effect of CCh on I_K(ACh) was occluded in colchicine-treated cells. Colchicine treatment, per se, may increase I_K(ACh) by -subunits released from G_s to mask this effect of CCh. Microtubules suppress I_Ca regulation by _i; their disruption releases restraints that unmask muscarinic inhibition of I_Ca. Summarily, colchicine treatment reverses regulation of ventricular excitation-contraction coupling by autonomic agents.

cytoskeleton; excitation-contraction coupling; colchicine

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