ATP-Sensitive Potassium Channels in Health and Disease

Abstract

The ATP-sensitive potassium (K(ATP)) channel plays a crucial role in insulin secretion and thus glucose homeostasis. K(ATP) channel activity in the pancreatic beta-cell is finely balanced; increased activity prevents insulin secretion, whereas reduced activity stimulates insulin release. The beta-cell metabolism tightly regulates K(ATP) channel gating, and if this coupling is perturbed, two distinct disease states can result. Diabetes occurs when the K(ATP) channel fails to close in response to increased metabolism, whereas congenital hyperinsulinism results when K(ATP) channels remain closed even at very low blood glucose levels. In general there is a good correlation between the magnitude of K(ATP) current and disease severity. Mutations that cause a complete loss of K(ATP) channels in the beta-cell plasma membrane produce a severe form of congenital hyperinsulinism, whereas mutations that partially impair channel function produce a milder phenotype. Similarly mutations that greatly reduce the ATP sensitivity of the K(ATP) channel lead to a severe form of neonatal diabetes with associated neurological complications, whilst mutations that cause smaller shifts in ATP sensitivity cause neonatal diabetes alone. This chapter reviews our current understanding of the pancreatic beta-cell K(ATP) channel and highlights recent structural, functional and clinical advances.

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…K ATP channels exist in several tissues, including brain, pancreas, and smooth and skeletal muscles, and their physiologic role has been mostly characterized in pancreatic beta cells. As mentioned above, the resting potential in beta cells is principally determined by K ATP channels (Clark and Proks, 2010). In the absence of glucose, beta cells are electrically silent because the K ATP activity is high (3 nS) and K 1 efflux is maintained.…”

“…1), and this combination is also present in alpha and delta cells from the islet (Clark and Proks, 2010;Ashcroft and Rorsman, 2013). Kir6.2 is a member of the inward rectifier potassium channels superfamily formed by two transmembrane domains, M1 and M2.…”

Enhancement of Ca2+Influx and Ciliary Beating by Membrane Hyperpolarization due to ATP-Sensitive K+Channel Opening in Mouse Airway Epithelial Cells

“…Initially, K ATP channels were identified as the key molecules for insulin secretion in pancreatic b-cells; they are now well known to be ubiquitously expressed in a variety of tissues as the molecular combination of channel-forming Kir6.x subunits and sulfonylurea receptors (SURs) (Clark and Proks, 2010;Flagg et al, 2010;Hibino et al, 2010). Although the expression of K ATP channels has been reported in alveolar cells (Trinh et al, 2007) and cell lines derived from human airway epithelial tissues (Trinh et al, 2008), their functional expression in ciliary cells has not yet been documented.…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…(7,27,29,77,84,110,111,136,138). K ATP channels are made of four pore-forming Kir (inward rectifier K + channel) subunits and four regulatory sulphonylurea receptors of the ATP-binding cassette (SUR) subunits (102 (137,138).…”