Roscovitine inhibits Ca V3.1 (T-type) channels by preferentially affecting closed-state inactivation

Document Type

Article

Publication Title

Journal of Pharmacology and Experimental Therapeutics

Abstract

T-type calcium channels (Ca V3) play an important role in many physiological and pathological processes, including cancerogenesis. Ca V3 channel blockers have been proposed as potential cancer treatments. Roscovitine, a trisubstituted purine, is a cyclin-dependent kinase (CDK) inhibitor that is currently undergoing phase II clinical trials as an anticancer drug and has been shown to affect calcium and potassium channel activity. Here, we investigate the effect of roscovitine on Ca V3.1 channels. Ca V3.1 channels were transiently expressed in human embryonic kidney 293 cells, and currents were recorded by using the whole-cell patch-clamp technique. Roscovitine blocks Ca V3.1 channels with higher affinity for depolarized cells (EC 50 of 10 μM), which is associated with a negative shift in the voltage dependence of closed-state inactivation. Enhanced inactivation is mediated by roscovitine-induced acceleration of closedstate inactivation and slowed recovery from inactivation. Small effects of roscovitine were also observed on T-channel deactivation and open-state inactivation, but neither could explain the inhibitory effect. Roscovitine inhibits Ca V3.1 channels within the therapeutic range (10-50 μM) in part by stabilizing the closed-inactivated state. The ability of roscovitine to block multiple mediators of proliferation, including CDKs and Ca V3.1 channels, may facilitate its anticancer properties. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.

First Page

463

Last Page

472

DOI

10.1124/jpet.111.187104

Publication Date

2-1-2012

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