Toward Linking Structure With Function in ATP-Sensitive K+ Channels

Abstract

Advances in understanding the overall structural features of inward rectifiers and ATP-binding cassette (ABC) transporters are providing novel insight into the architecture of ATP-sensitive K ؉ channels (K ATP channels) (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 glibenclamide/sulfonylurea binding pocket. Consistent with 30-year-old studies on the pharmacology of hypoglycemic agents, the pocket is bipartite. Elements of the COOHterminal 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 -terminus. Diabetes 53 (Suppl. 3):S104 -S112, 2004 T he regulation of insulin secretion from pancreatic ␤-cells in the islets of Langerhans is under the orchestration of multiple conductors. While glucose metabolism and changes in cellular energy 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. Understanding the molecular basis of these inputs provides multiple routes for therapeutic intervention to both augment and diminish insulin secretion in disorders of glucose homeostasis. The ionic pathway, particularly ATPsensitive K ϩ 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 Loubatiè 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 glucose metabolism. The activity of K ATP channels is modulated 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 ϳ10 mol/l) inhibits activity. This inhibition can be antagonized by MgADP acting through the sulfonylurea receptor (SUR). The coupling of membrane potential with cellular metabolism provides a means to adjust the activity of voltagegated Ca 2ϩ channels and, thus, modulate Ca 2ϩ -dependent insulin exocytosis. K ATP channels are known targets for hypoglycemic sulfonylureas like tolbutamide and glibenclamide and for nonsulfonylureas like nateglinide and repaglinide, which increase insulin ...

Both Gi and Go Heterotrimeric G Proteins Are Required to Exert the Full Effect of Norepinephrine on the β-Cell KATP Channel

“…K ATP channels are formed from an inward rectifier potassium channel (Kir6.x) and a sulfonylurea receptor (SUR) subunit, arranged with 4:4 stoichiometry (38,39). The different isoforms of Kir6.x (Kir6.1 or Kir6.2) and SUR (SUR1, SUR2A, or SUR2B) show distinct expression patterns.…”

Phosphorylation-dependent Changes in Nucleotide Binding, Conformation, and Dynamics of the First Nucleotide Binding Domain (NBD1) of the Sulfonylurea Receptor 2B (SUR2B)

“…Binding of MgATP leads to dimerization of the NBD1 and NBD2, which dissociate upon MgATP hydrolysis (6). In addition to the minimum ABC protein structure, the SUR proteins contain a third membrane spanning domain (MSD0) that is linked to the N terminus of MSD1 by the cytoplasmic L0 linker (7)(8)(9)(10). Unlike most members of the family, SUR proteins possess no known transporter activity but instead regulate gating of the Kir6.x pore.…”

Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

“…ATP-sensitive K + channels (K ATP channels) are tetradimers composed of pore-forming subunits (inwardly rectifying K + channel [Kir6.x]) and sulfonylurea receptors (SURx), which act as regulatory subunits [1][2][3]. They have the unique property of being closed by intracellular ATP and opened by MgADP and other nucleoside diphosphates, thereby linking cell metabolism to excitability.…”