Physiological and pathophysiological roles of ATP-sensitive K+ channels

Abstract

ATP-sensitive potassium (K(ATP)) channels are present in many tissues, including pancreatic islet cells, heart, skeletal muscle, vascular smooth muscle, and brain, in which they couple the cell metabolic state to its membrane potential, playing a crucial role in various cellular functions. The K(ATP) channel is a hetero-octamer comprising two subunits: the pore-forming subunit Kir6.x (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptor SUR (SUR1 or SUR2). Kir6.x belongs to the inward rectifier K(+) channel family; SUR belongs to the ATP-binding cassette protein superfamily. Heterologous expression of differing combinations of Kir6.1 or Kir6.2 and SUR1 or SUR2 variant (SUR2A or SUR2B) reconstitute different types of K(ATP) channels with distinct electrophysiological properties and nucleotide and pharmacological sensitivities corresponding to the various K(ATP) channels in native tissues. The physiological and pathophysiological roles of K(ATP) channels have been studied primarily using K(ATP) channel blockers and K(+) channel openers, but there is no direct evidence on the role of the K(ATP) channels in many important cellular responses. In addition to the analyses of naturally occurring mutations of the genes in humans, determination of the phenotypes of mice generated by genetic manipulation has been successful in clarifying the function of various gene products. Recently, various genetically engineered mice, including mice lacking K(ATP) channels (knockout mice) and mice expressing various mutant K(ATP) channels (transgenic mice), have been generated. In this review, we focus on the physiological and pathophysiological roles of K(ATP) channels learned from genetic manipulation of mice and naturally occurring mutations in humans.

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

“…Biogenesis of the heteromultimeric K ATP channel occurs through combinations of subunit isoforms that define the intrinsic properties and tissue specificity of the channel complex [3,4]. Physical association of the Kir6.2 and SUR2A isoforms generates cardiac K ATP channels that are expressed in high density at the sarcolemma [5,6].…”

Molecular analysis of the subtype‐selective inhibition of cloned KATP channels by PNU‐37883A

“…K ATP channels play key roles in several vital physiological functions, including insulin secretion by the pancreas, protection of cardiac muscle during ischaemia and hypoxic vasodilatation of arterial smooth muscle (reviewed by Seino & Miki, 2003). They are composed of hetero-octamers of four pore-forming Kir6.0 and four sulphonylurea receptor (SUR) subunits (Clement et al, 1997;Inagaki et al, 1997;Shyng & Nichols, 1997).…”

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

“…K ATP channels consist of pore-forming Kir6.x subunits that associate with different kinds of regulatory sulphonylurea receptor subunits: SUR1, SUR2A or SUR2B [7]. The beta-cell K ATP channel is composed of Kir6.2 and SUR1 [8,9], the cardiac type of Kir6.2 and SUR2A [10], and the vascular smooth muscle type of Kir6.1 and SUR2B [11].…”

“…It is believed that Kir6.2 and SUR2B make up some smooth muscle K ATP channels [12], and that both Kir6.2/SUR1 and Kir6.2/SUR2B combinations are found in neurones [13]. SUR acts as a channel regulator, with the different SUR subtypes conferring differential sensitivity to the inhibitory effects of sulphonylurea drugs and the stimulatory actions of KCOs and MgADP [7,14]. For example, diazoxide strongly activates beta cell and smooth muscle K ATP channels but has only a weak stimulatory effect on cardiac K ATP channels [15,16,17,18].…”