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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