Abstract
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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.110593.
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ABBREVIATIONS: hERG, human ether-a-go-go-related gene; IKr, rapidly activating delayed rectifier potassium current; RPR260243, (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid, PD-118057, 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid, and NS1643, 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea; MTX, mallotoxin; PKC, protein kinase C; CHO, Chinese hamster ovary; I-V, current-voltage relationship.
- Received July 10, 2006.
- Accepted August 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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