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Coassembly of Different Sulfonylurea Receptor Subtypes Extends the Phenotypic Diversity of ATP-sensitive Potassium (K_ATP) Channels

Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio (A.W., K.Y., K.F., K.D., S.L., K.W.C.); Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania (C.W., A.M.S., U.M., T.M.); and Institut de Biologie Structurale, Grenoble, France (C.M., J.R., M.V.).

K_ATP channels are metabolic sensors and targets of potassium channel openers (KCO; e.g., diazoxide and pinacidil). They comprise four sulfonylurea receptors (SUR) and four potassium channel subunits (Kir6) and are critical in regulating insulin secretion. Different SUR subtypes (SUR1, SUR2A, SUR2B) largely determine the metabolic sensitivities and the pharmacological profiles of K_ATP channels. SUR1- but not SUR2-containing channels are highly sensitive to metabolic inhibition and diazoxide, whereas SUR2 channels are sensitive to pinacidil. It is generally believed that SUR1 and SUR2 are incompatible in channel coassembly. We used triple tandems, T1 and T2, each containing one SUR (SUR1 or SUR2A) and two Kir6.226 (last 26 residues are deleted) to examine the coassembly of different SUR. When T1 or T2 was expressed in Xenopus laevis oocytes, small whole-cell currents were activated by metabolic inhibition (induced by azide) plus a KCO (diazoxide for T1, pinacidil for T2). When coexpressed with any SUR subtype, the activated-currents were increased by 2- to 13-fold, indicating that different SUR can coassemble. Consistent with this, heteromeric SUR1+SUR2A channels were sensitive to azide, diazoxide, and pinacidil, and their single-channel burst duration was 2-fold longer than that of the T1 channels. Furthermore, SUR2A was coprecipitated with SUR1. Using whole-cell recording and immunostaining, heteromeric channels could also be detected when T1 and SUR2A were coexpressed in mammalian cells. Finally, the response of the SUR1+SUR2A channels to azide was found to be intermediate to those of the homomeric channels. Therefore, different SUR subtypes can coassemble into K_ATP channels with distinct metabolic sensitivities and pharmacological profiles.

Address correspondence to: Kim W. Chan, Department of Pharmacological Sciences, CV Therapeutics, 1651 Page Mill Rd, Palo Alto, CA 94304. E-mail: kim.chan{at}cvt.com