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First published on November 27, 2007; DOI: 10.1124/mol.107.041152

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Received for publication August 23, 2007.
Revised November 19, 2007.
Accepted for publication November 21, 2007.

PD-307243 Causes Instantaneous Current Through Human Ether-a-go-go-Related Gene (hERG) Potassium Channels

Earl Gordon 1, Irina M Lozinskaya 1, Zuojun Lin 1, Simon F Semus 2, Frank E Blaney 2, Robert N Willette 1, Xiaoping Xu 1*

1 Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline 2 Department of Computational and Structural Sciences, GlaxoSmithKline

* Address correspondence to: E-mail: xiaoping.2.xu{at}gsk.com

Abstract

Long and short QT syndromes associated with loss and gain of hERG channel activity, respectively, can cause life threatening arrhythmias. As such, modulation of hERG channel activity is an important consideration in the development of all new therapeutic agents. In the present study we investigated the mechanisms of action of PD-307243, a known hERG channel activator, on hERG channels stably expressed in CHO cells using the patch-clamp technique. In the whole-cell recordings, the extracellular application of PD-307243 concentration-dependently increased the hERG current and markedly slowed hERG channel deactivation and inactivation. PD-307243 (3 and 10 µM) induced instantaneous hERG current with little decay at membrane potentials from -120 to -40 mV. At more positive voltages, PD-307243 induced an Ito-like upstroke of hERG current. The activity of PD-307243 was use-dependent, requiring the opening of hERG channels. The actions of PD-307243 on the rapid component of delayed rectifier K+ current (IKr) in rabbit ventricular myocytes were similar to those observed in hERG transfected CHO cells. Inside-out patch experiments revealed that PD-307243 increased hERG tail currents by 2.1±0.6 (n=7) and 3.4±0.3 fold (n=4) at 3 and 10 µM, respectively, by slowing the channel deactivation but had no effect on channel activation. During a voltage-clamp protocol using a prerecorded cardiac action potential, 3 µM PD-307243 increased the total potassium ions passed through hERG channels by 8.8±1.0 fold (n=5). Docking studies suggest that PD-307243 interacts with residues in the S5-P region of the channel.


Key words: Ion channel regulation, Potassium, Structure-activity relationships and modeling


This article has been cited by other articles:


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X. Xu, M. Recanatini, M. Roberti, and G.-N. Tseng
Probing the Binding Sites and Mechanisms of Action of Two Human Ether-a-go-go-Related Gene Channel Activators, 1,3-bis-(2-Hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD307243)
Mol. Pharmacol., June 1, 2008; 73(6): 1709 - 1721.
[Abstract] [Full Text] [PDF]


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