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First published on July 6, 2006; DOI: 10.1124/mol.106.026492

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Received for publication May 16, 2006.
Revised July 4, 2006.
Accepted for publication July 5, 2006.

Biophysical characterization of the new HERG1 channel opener NS3623

Rie Schultz Hansen 1, Thomas Goldin Diness 1, Torsten Christ 2, Erich Wettwer 2, Ursula Ravens 2, Soren-Peter Olesen 1, Morten Grunnet 1*

1 NeuroSearch A/S and The Danish National Research Foundation Centre for Cardiac Arrhythmia 2 Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology

* Address correspondence to: E-mail: mgr{at}neurosearch.dk

Abstract

Abstract Within the field of new anti-arrhythmic compounds the interesting idea of activating HERG1 potassium channels has recently been introduced. Potentially, drugs that increase HERG1 channel activity will augment the repolarising current of the cardiac myocytes and stabilize the diastolic interval. This might make the myocardium more resistant to events that causes arrhythmias. We here present the compound NS3623 that has the ability to activate HERG1 channels expressed in Xenopus laevis oocytes with an EC50 value of 79.4 µM. Exposure of HERG1 channels to NS3623 affects the voltage dependent release from inactivation, resulting in a half inactivation voltage that is right-ward shifted by 17.7 mV. Moreover the compound is affecting the time constant of inactivation leading to a slower on-set of inactivation of the macroscopic HERG1 currents. We also characterized the ability of NS3623 to increase the activity of different mutated HERG1 channels. The mutants S620T and S631A are severely compromised in their ability to inactivate. Application of NS3623 to any of these two mutants did not result in increased HERG1 current. In contrast, application of NS3623 to the mutant F656M increased HERG1 current to a larger extent than what was observed with wild-type HERG1 channels. Since the amino acid F656 is essential for high affinity inhibition of HERG1 channels it is concluded that NS3623 has a dual mode of action being both an activator and an inhibitor of HERG1 channels. Finally, we demonstrate that NS3623 has the ability to shorten action potential durations in guinea pig papillary muscle.


Key words: Ion channel regulation, Potassium, Func. analysis receptor/ion channel mutants


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