QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.038331v1 72/4/1033    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bentzen, B. H. Articles by Grunnet, M. Search for Related Content PubMed PubMed Citation Articles by Bentzen, B. H. Articles by Grunnet, M.

The Small Molecule NS11021 Is a Potent and Specific Activator of Ca²⁺-Activated Big-Conductance K⁺ Channels

The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, the Panum Institute, Copenhagen, Denmark (B.H.B., K.C., S.-P.O., M.G.); and NeuroSearch A/S, Ballerup, Denmark (A.N., L.S.M., S.-P.O., M.G.)

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, 1-(3,5-bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea (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 activated 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 (10 µM) influenced neither 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 with 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.

Address correspondence to: Morten Grunnet, NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark. E-mail: mgr{at}neurosearch.dk

This article has been cited by other articles:

				B. Eichhorn, G. Muller, A. Leuner, T. Sawamura, U. Ravens, and H. Morawietz Impaired vascular function in small resistance arteries of LOX-1 overexpressing mice on high-fat diet Cardiovasc Res, June 1, 2009; 82(3): 493 - 502. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]