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Vol. 62, Issue 3, 554-565, September 2002

Genistein Inhibits Cardiac L-Type Ca2+ Channel Activity by a Tyrosine Kinase-Independent Mechanism

Andriy E. Belevych, Sunita Warrier, and Robert D. Harvey

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio

It has been suggested that protein tyrosine kinase (PTK) activity can directly regulate cardiac L-type Ca2+ channels. This conclusion is based to a large extent on the observation that the PTK inhibitor genistein can inhibit the cardiac L-type Ca2+ current. The purpose of the present study was to determine whether the ability of genistein to inhibit cardiac L-type Ca2+ channel activity is due to inhibition of PTK activity. Genistein significantly reduced the magnitude of the L-type Ca2+ current in guinea pig ventricular myocytes recorded using the whole-cell patch-clamp technique. However, this effect was associated with extracellular, not intracellular, application of the drug. Peroxovanadate (PVN), a potent protein tyrosine phosphatase inhibitor, had no effect on the basal Ca2+ current. PVN was also ineffective in preventing the inhibitory effect of genistein. Internal perfusion of cells with a pipette solution containing ATPgamma S was used to prevent reversibility of phosphorylation-dependent processes. This treatment did not alter the inhibitory effect of genistein, although it did result in irreversible protein kinase A-dependent regulation of the Ca2+ current. Bath application of lavendustin A, a PTK inhibitor that is structurally unrelated to genistein, did not affect the Ca2+ current amplitude. The inhibitory effect of genistein was also associated with a hyperpolarizing shift in the voltage dependence of Ca2+ channel inactivation. These results are consistent with the conclusion that the cardiac L-type Ca2+ current is not directly regulated by PTK activity and that the inhibitory effect of genistein is due to direct non-catalytic blockade of the channels.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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