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Concerted Gating Mechanism Underlying K_ATP Channel Inhibition by ATP

Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Correspondence: Address reprint requests to Peter Drain, Biomedical Science Tower Rm. 323, 3500 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9412; Fax: 412-648-8792; E-mail: drain{at}pitt.edu.

K_ATP channels assemble from four regulatory SUR1 and four pore-forming K_ir6.2 subunits. At the single-channel current level, ATP-dependent gating transitions between the active burst and the inactive interburst conformations underlie inhibition of the K_ATP channel by intracellular ATP. Previously, we identified a slow gating mutation, T171A in the K_ir6.2 subunit, which dramatically reduces rates of burst to interburst transitions in K_ir6.2C26 channels without SUR1 in the absence of ATP. Here, we constructed all possible mutations at position 171 in K_ir6.2C26 channels without SUR1. Only four substitutions, 171A, 171F, 171H, and 171S, gave rise to functional channels, each increasing K_i,ATP for ATP inhibition by >55-fold and slowing gating to the interburst by >35-fold. Moreover, we investigated the role of individual K_ir6.2 subunits in the gating by comparing burst to interburst transition rates of channels constructed from different combinations of slow 171A and fast T171 "wild-type" subunits. The relationship between gating transition rate and number of slow subunits is exponential, which excludes independent gating models where any one subunit is sufficient for inhibition gating. Rather, our results support mechanisms where four ATP sites independently can control a single gate formed by the concerted action of all four K_ir6.2 subunit inner helices of the K_ATP channel.

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