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CELLULAR AND MOLECULAR

Mallotoxin Is a Novel Human Ether-a-go-go-Related Gene (hERG) Potassium Channel Activator

Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania

Human ether-a-go-go-related gene (hERG) encodes a rapidly activating delayed rectifier potassium channel that plays important roles in cardiac action potential repolarization. Although many drugs and compounds block hERG channels, activators of the channel have only recently been described. Three structurally diverse synthetic compounds have been reported to activate hERG channels by altering deactivation or inactivation or by unidentified mechanisms. Here, we describe a novel, naturally occurring hERG channel activator, mallotoxin (MTX). The effects of MTX on hERG channels were investigated using the patch-clamp technique. MTX increased both step and tail hERG currents with EC₅₀ values of 0.34 and 0.52 µM, respectively. MTX leftward shifted the voltage dependence of hERG channel activation to less depolarized voltages (24 mV at 2.5 µM). In addition, MTX increased hERG deactivation time constants. MTX did not change the half-maximal inactivation voltage of the hERG channel, but it reduced the slope of the voltage-dependent inactivation curve. All of these factors contribute to the enhanced activity of hERG channels. During a voltage-clamp protocol using prerecorded cardiac action potentials, 2.5 µM MTX increased the total potassium ions passed through hERG channels by 5-fold. In conclusion, MTX activates hERG channels through distinct mechanisms and with significantly higher potency than previously reported hERG channel activators.

Address correspondence to: Dr. Xiaoping Xu, GlaxoSmithKline, 709 Swedeland Rd., UW2511, P.O. Box 1539, King of Prussia, PA 19406. E-mail: Xiaoping.2.Xu{at}gsk.com

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