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¹ Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
² Department of Pharmacology and Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Correspondence to Peter Drain: drain{at}pitt.edu

Major advances have been made on the inhibition gate and ATP site of the K_ir6.2 subunit of the K_ATP channel, but little is known about conformational coupling between the two. ATP site mutations dramatically disrupt ATP-dependent gating without effect on ligand-independent gating, observed as interconversions between active burst and inactive interburst conformations in the absence of ATP. This suggests that linkage between site and gate is conditionally dependent on ATP occupancy. We studied all substitutions at position 334 of the ATP site in K_ir6.2C26 that express in Xenopus oocytes. All substitutions disrupted ATP-dependent gating by 10-fold or more. Only positive-charged arginine or lysine at 334, however, slowed ligand-independent gating from the burst, and this was in some but not all patches. Moreover, the polycationic peptide protamine reversed the slowed gating from the burst of 334R mutant channels, and speeded the slow gating from the burst of wild-type SUR1/K_ir6.2 in the absence of ATP. Our results support a two-step ligand-dependent linkage mechanism for K_ir6.2 channels in which ATP-occupied sites function to electrostatically dissociate COOH-terminal domains from the membrane, then as in all K_ir channels, free COOH-terminal domains and inner M2 helices transit to a lower energy state for gate closure.

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