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First published on July 16, 2007; DOI: 10.1124/mol.107.038331

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Received for publication May 22, 2007.
Revised July 12, 2007.
Accepted for publication July 16, 2007.

The small molecule NS11021 is a potent and specific activator of Ca2+-activated Big Conductance K+ channels

Bo Hjorth Bentzen 1, Antonio Nardi 2, Kirstine Calloe 1, Lars Siim Madsen 2, Soren Peter Olesen 1, Morten Grunnet 2*

1 University of Copenhagen 2 NeuroSearch A/S

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

Abstract

Large-conductance Ca2+- and voltage-activated K+ channels (KCa1.1/BK/MaxiK) are widely expressed ion channels. They provide a Ca2+-dependent feedback mechanism for the regulation of various body functions such as blood flow, neurotransmitter release, uresis and immunity. In addition, a mitochondrial K+ channel with KCa1.1 resembling properties has been found in the heart, where it may be involved in regulation of energy consumption. In the present study the effect of a novel NeuroSearch compound, NS11021, was investigated on cloned KCa1.1 expressed in Xenopus laevis oocytes and mammalian cells using electrophysiological methods. NS11021 at concentrations above 0.3 µM activates KCa1.1 in a concentration-dependent manner by parallel-shifting the channel activation curves to more negative potentials. Single-channel analysis revealed that NS11021 increased the open probability of the channel by altering gating kinetics without affecting the single-channel conductance. NS11021 did neither influence a number of cloned Kv channels nor endogenous Na+ and Ca2+ channels (L- and T-type) in guinea pig cardiac myocytes. In conclusion, NS11021 is a novel KCa1.1 channel activator with better specificity and a 10 times higher potency compared to the most broadly applied KCa1.1 opener NS1619. Thus NS11021 might be a valuable tool compound when addressing the physiological and pathophysiological roles of KCa1.1 channels.


Key words: Ion channel regulation, Potassium, Ischemia/Reperfusion


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S.-N. Wu, H. Peng, B.-S. Chen, Y.-J. Wang, P.-Y. Wu, and M.-W. Lin
Potent Activation of Large-Conductance Ca2+-Activated K+ Channels by the Diphenylurea 1,3-Bis-[2-hydroxy-5-(trifluoromethyl)phenyl]urea (NS1643) in Pituitary Tumor (GH3) Cells
Mol. Pharmacol., December 1, 2008; 74(6): 1696 - 1704.
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