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Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey (L.Y., J.H., P.M.D., R.M.Bu., R.S.S., P.B., R.M.Br., B.T.P., G.J.K., M.L.G.); and Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York (E.G., B.R.)
Abstract
Voltage-gated potassium (Kv) channels regulate many physiological functions and represent important therapeutic targets in the treatment of several clinical disorders. Although some of these channels have been well-characterized, the study of others, such as Kv3 channels, has been hindered because of limited pharmacological tools. The current study was initiated to identify potent blockers of the Kv3.2 channel. Chinese hamster ovary (CHO)-K1 cells stably expressing human Kv3.2b (CHO-K1.hKv3.2b) were established and characterized. Stichodactyla helianthus peptide (ShK), isolated from S. helianthus venom and a known high-affinity blocker of Kv1.1 and Kv1.3 channels, was found to potently inhibit 86Rb+ efflux from CHO-K1.hKv3.2b (IC50 
0.6 nM). In electrophysiological recordings of Kv3.2b channels expressed in Xenopus laevis oocytes or in planar patch-clamp studies, ShK inhibited hKv3.2b channels with IC50 values of 0.3 and 6 nM, respectively. Despite the presence of Kv3.2 protein in human pancreatic 
cells, ShK has no effect on the Kv current of these cells, suggesting that it is unlikely that homotetrameric Kv3.2 channels contribute significantly to the delayed rectifier current of insulin-secreting cells. In mouse cortical GABAergic fast-spiking interneurons, however, application of ShK produced effects consistent with the blockade of Kv3 channels (i.e., an increase in action potential half-width, a decrease in the amplitude of the action potential after hyperpolarization, and a decrease in maximal firing frequency in response to depolarizing current injections). Taken together, these results indicate that ShK is a potent inhibitor of Kv3.2 channels and may serve as a useful pharmacological probe for studying these channels in native preparations.
Address correspondence to: Dr. Maria L. Garcia, Department of Ion Channels, Merck Research Laboratories, RY80N-C31, Rahway, NJ 07065. E-Mail: maria_garcia{at}merck.com
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