Toward Linking Structure With Function in ATP-Sensitive K  Channels Joseph Bryan, 1 Wanda H. Vila-Carriles, 2 Guiling Zhao, 1 Audrey P. Babenko, 1 and Lydia Aguilar-Bryan 1,3 Advances in understanding the overall structural fea- tures of inward rectifiers and ATP-binding cassette (ABC) transporters are providing novel insight into the architecture of ATP-sensitive K  channels (K ATP chan- nels) (K IR 6.0/SUR) 4 . The structure of the K IR pore has been modeled on bacterial K  channels, while the lipid-A exporter, MsbA, provides a template for the MDR-like core of sulfonylurea receptor (SUR)-1. TMD0, an NH 2 - terminal bundle of five -helices found in SURs, binds to and activates K IR 6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the K IR 6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH 2 -terminus of the K IR . Homology modeling of the SUR1 core offers the possibility of defining the gliben- clamide/sulfonylurea binding pocket. Consistent with 30- year-old studies on the pharmacology of hypoglycemic agents, the pocket is bipartite. Elements of the COOH- terminal half of the core recognize a hydrophobic group in glibenclamide, adjacent to the sulfonylurea moiety, to provide selectivity for SUR1, while the benzamido group appears to be in proximity to L0 and the K IR NH 2 -termi- nus. Diabetes 53 (Suppl. 3):S104 –S112, 2004 T he regulation of insulin secretion from pancre- atic -cells in the islets of Langerhans is under the orchestration of multiple conductors. While glucose metabolism and changes in cellular en- ergy status ultimately drive insulin output, a variety of inputs converge to modify the rate of secretion and thus maintain blood glucose levels within normal limits. Under- standing the molecular basis of these inputs provides multiple routes for therapeutic intervention to both aug- ment and diminish insulin secretion in disorders of glu- cose homeostasis. The ionic pathway, particularly ATP- sensitive K + channels (K ATP channels), has been an effective target, based on the observations by Janbon and colleagues that treatment with a sulfonamide, 2254 RP, produced severe hypoglycemia, as well as subsequent studies by Loubatie ` res that the RP compound stimulated insulin release (rev. in 1–3). In pancreatic -cells, K ATP channels are part of the ionic triggering mechanism that increases insulin secretion in response to increased glu- cose metabolism. The activity of K ATP channels is modu- lated by changes in the ATP/ADP ratio. In the absence of nucleotides, these channels are spontaneously active, but binding of ATP to the K IR subunits (the half-maximal inhibitory concentration [IC 50 ] for ATP is 10 mol/l) inhibits activity. This inhibition can be antagonized by MgADP acting through the sulfonylurea receptor (SUR). The coupling of membrane potential with cellular metab- olism provides a means to adjust the activity of voltage- gated Ca 2+ channels and, thus, modulate Ca 2+ -dependent insulin exocytosis. K ATP channels are known targets for hypoglycemic sulfonylureas like tolbutamide and gliben- clamide and for nonsulfonylureas like nateglinide and repaglinide, which increase insulin output by reducing K + channel activity, thus modulating intracellular free Ca 2+ ([Ca 2+ ] i ) (4). The physiologic importance of the ionic mechanism is well illustrated by the dramatic changes in glucose ho- meostasis that can result from genetic alterations, which affect the P O —the probability that K ATP channels are in the open state. This is shown conceptually in Fig. 1, which relates the P O to -cell membrane potential and insulin secretion. Depolarization activates voltage-gated Ca 2+ channels, induces oscillation of cytosolic [Ca 2+ ] i , and thus pulsatile release of insulin (5,6). In humans, the loss of SUR1/K IR 6.2 K ATP channel activity is the most common cause of persistent hyperinsulinemic hypoglycemia when -cells are persistently depolarized and oversecrete insulin (rev. in 7,8). A mild dominant form of hypoglycemia due to a mutation in SUR1, Glu1507Lys, produces hyperinsulin- ism at an early age and then progresses to decreased insulin secretory capacity in early adulthood and diabetes in middle age (9). At the other extreme, overexpression of a mutant pore subunit, engineered to activate channels by decreasing their sensitivity to inhibitory ATP, resulted in transgenic mice with neonatal diabetes (10). These results implied that “gain-of-activity” mutations were candidates for producing neonatal diabetes, and a genetic screen of patients identified mutations at two NH 2 -terminal and two COOH-terminal positions (Q52, V59, R201, and I296) in K IR 6.2 associated with permanent neonatal diabetes (11). From the 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; the 2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas; and the 3 Department of Medicine, Baylor College of Medicine, Houston, Texas. Address correspondence and reprint requests to Joseph Bryan, PhD, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. E-mail: jbryan@bcm.tmc.edu. Received for publication 13 March 2004 and accepted in revised form 12 May 2004. This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educa- tional grant from Servier. ABC, ATP-binding cassette; [Ca 2+ ] i , intracellular Ca 2+ concentration; ER, endoplasmic reticulum; ICD, intracellular coupling domain; K ATP channel, ATP-sensitive K + channel; K IR channel, inwardly rectifying K + channel; MDR, multidrug resistance protein; NBD, nucleotide-binding fold; P O , open proba- bility; SUR, sulfonylurea receptor; TMD, transmembrane domain. © 2004 by the American Diabetes Association. S104 DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004