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Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):347-62. doi: 10.1016/j.pbiomolbio.2009.01.002. Epub 2009 Jan 24.

hERG1 channel activators: a new anti-arrhythmic principle.

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1
NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. mgr@neurosearch.dk <mgr@neurosearch.dk>

Abstract

The cardiac action potential is the result of an orchestrated function of a number of different ion channels. Action potential repolarisation in humans relies on three potassium current components named I(Kr), I(Ks) and I(K1) with party overlapping functions. The ion channel alpha-subunits conducting these currents are hERG1 (Kv11.1), KCNQ1 (Kv7.1) and Kir2.1. Loss-of-function in any of these currents can result in long QT syndrome. Long QT is a pro-arrhythmic disease with increased risk of developing lethal ventricular arrhythmias such as Torsade de Pointes and ventricular fibrillation. In addition to congenital long QT, acquired long QT can also constitute a safety risk. Especially unintended inhibition of the hERG1 channel constitutes a major concern in the development of new drugs. Based on this knowledge is has been speculated whether activation of the hERG1 channel could be anti-arrhythmic and thereby constitute a new principle in treatment of cardiac arrhythmogenic disorders. The first hERG1 channel agonist was reported in 2005 and a limited number of such compounds are now available. In the present text we review results obtained by hERG1 channel activation in a number of cardiac relevant settings from in vitro to in vivo. It is demonstrated how the principle of hERG1 channel activation under certain circumstances can constitute a new anti-arrhythmogenic principle. Finally, important conceptual differences between the short QT syndrome and the hERG1 channel activation, are evaluated.

[Indexed for MEDLINE]

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