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(Circulation Research. 2001;88:e32.)
© 2001 American Heart Association, Inc.

Research Commentary

Modulation of Ca²⁺ Signaling by Microtubule Disruption in Rat Ventricular Myocytes and Its Dependence on the Ruptured Patch-Clamp Configuration

S. C. Calaghan, J.-Y. Le Guennec, E. White

From the School of Biomedical Sciences (S.C.C., E.W.), University of Leeds, Leeds, UK; Nutrition, Croissance, Cancer EA2103 (J.-Y.G.), University of Tours, Tours, France.

Correspondence to Dr S. Calaghan, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. E-mail s.c.calaghan{at}leeds.ac.uk

Abstract—In the absence of hypertrophic proliferation of microtubules, microtubule disruption by colchicine does not modulate contraction of adult cardiac myocytes. However, Gomez et al (Circ Res. 2000;86:30–36) recently reported that disruption of microtubules by colchicine in ruptured patch-clamped myocytes increased I_Ca,L density and [Ca²⁺]_i transient amplitude and depressed the response of these parameters to the ß-adrenoceptor agonist isoproterenol. These effects were ascribed to stimulation of adenylyl cyclase by increased intracellular free tubulin. In the present study, we show that in intact rat ventricular myocytes, 2 to 4 hours of exposure to 10 µmol/L colchicine had no effect on shortening or [Ca²⁺]_i transient amplitude or on the amplitude of I_Ca,L in perforated patch-clamped cells, under basal conditions and after stimulation with 1 µmol/L isoproterenol. However, in ruptured patch-clamped myocytes, basal I_Ca,L was 2-fold higher after treatment with colchicine compared with vehicle and, in contrast to vehicle-treated cells, I_Ca,L did not increase in response to isoproterenol. Cell width decreased during ruptured patch-clamp experiments in colchicine-treated but not vehicle-treated myocytes. We conclude that in cells with intact sarcolemma, colchicine does not modulate Ca²⁺ signaling or the response to ß stimulation. However, the combination of microtubule disruption by colchicine and the ruptured patch configuration activates I_Ca,L and attenuates the response to ß stimulation. We propose that these effects may be due to loss of free tubulin by intracellular dialysis or to increased sensitivity to mechanical stimulation as a result of microtubule disruption. These findings have important implications for cardiomyopathies associated with decreased free tubulin or a diminished microtubular network. The full text of this article is available at http://www.circresaha.org.

Key Words: cardiac myocyte • contraction • calcium signaling • microtubules • colchicine

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