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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 14, 2008; DOI: 10.1124/jpet.107.134932

0022-3565/08/3252-507-512$20.00
JPET 325:507-512, 2008
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CARDIOVASCULAR

An Estrogen Metabolite, 2-Methoxyestradiol, Disrupts Cardiac Microtubules and Unmasks Muscarinic Inhibition of Calcium Current

Jian-Bing Shen, and Achilles J. Pappano

Department of Pharmacology (A.J.P.) and Calhoun Cardiology Center (J.-B.S., A.J.P.), University of Connecticut Health Center, Farmington, Connecticut

Microtubules provide a chemical signaling function as well as structural support for heart cells. Microtubules modulate autonomic signaling in the heart, and their disruption by colchicine unmasks muscarinic inhibition of Ca (ICa) current. In this study, we compare the actions of the estrogen metabolite, 2-methoxyestradiol (2-ME), with those of colchicine on microtubule stability and chemical signal function in guinea pig-isolated ventricular myocytes. Like colchicine, 2-ME binds to microtubules and disrupts the cytoskeleton of cardiac myocytes. Incubation with 2-ME increased the soluble fraction of tubulin and decreased the polymerized fraction at concentrations ranging from 10 to 100 µM. 2-ME was less potent than colchicine in causing microtubular disruption. Treatment with 2-ME for up to 4 h was accompanied by a progressive increase of ICa amplitude. There was no change in the rates of ICa inactivation. Carbachol, which has no effect on ICa in untreated ventricular myocytes, inhibited this current in the presence of 2-ME. The extent of inhibition increased with incubation time in 2-ME such that carbachol completely removed the increment of ICa by the estrogen metabolite. The results illustrate the important role of microtubules in modulating cardiac autonomic signaling.

Received December 7, 2007; accepted February 13, 2008.

Address correspondence to: Dr. Achilles J. Pappano, Department of Cell Biology, MC-6125, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. E-mail: pappano{at}nso1.uchc.edu






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