Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complic...

The sulphonylurea receptor (SUR) is a member of the ATP-binding cassette (ABC) family of membrane proteins. It functions as the regulatory subunit of the ATP-sensitive potassium (KATP) channel, which comprises SUR and Kir6.x proteins. Here, we review data demonstrating functional differences between the two nucleotide binding domains (NBDs) of SUR1. In addition, to explain the structural basis ...

Activating mutations in one of the two subunits of the ATP-sensitive potassium (KATP) channel cause neonatal diabetes (ND). This may be either transient or permanent and, in approximately 20% of patients, is associated with neurodevelopmental delay. In most patients, switching from insulin to oral sulfonylurea therapy improves glycemic control and ameliorates some of the neurological disabiliti...

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans...

ATP-sensitive K+ (KATP) channels play a crucial role in coupling cellular metabolism to membrane potential. In addition to the orthologs corresponding to Kir6.1 and Kir6.2 of mammals, we have identified a novel member, designated Kir6.3 (zKir6.3), of the inward rectifier K+ channel subfamily Kir6.x in zebrafish. zKir6.3 is a protein of 432 amino acids that shares 66% identity with mammalian Kir...

In mildly hyperosmotic medium, activation of the Na+ -K+ -2Cl- cotransporter (NKCC) counteracts skeletal muscle cell water loss, and compounds that stimulate protein kinase A (PKA) activity inhibit the activation of the NKCC. The aim of this study was to determine the mechanism for PKA inhibition of NKCC activity in resting skeletal muscle. Incubation of rat slow-twitch soleus and fast-twitch p...

Rioufol, Gilles, Michel Ovize, Joseph Loufoua, Calin Pop, Xavier André-Fouët, and Yves Minaire. Ventricular fibrillation in preconditioned pig hearts: role of KATP 1 channels. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2804– H2810, 1997.—ATP-dependent potassium (KATP 1 ) channels play a role in the infarct size-limiting effect of preconditioning in pigs. We previously demonstrated that pre...

Hypoxic coronary vasodilation contributes to the maintenance of oxygen supply to the working heart during increased metabolic demand. Mechanisms of hypoxic coronary dilation have been studied extensively and differ considerably depending upon the species and experimental model. In isolated coronary vessels, several mechanisms have been implicated either alone or in combination, including releas...

The ATP-sensitive K+ (KATP) channel is composed of a sulfonylurea receptor (SUR) and a pore-forming subunit, Kir6.2. SUR is an ATP-binding cassette (ABC) protein with two nucleotide-binding domains (NBD1 and NBD2). Intracellular ATP inhibits KATP channels through Kir6.2 and activates them through NBDs. However, it is still unknown how ATP-bound NBDs activate KATP channels. A prokaryotic ABC pro...

Although it is well established that ischemic preconditioning (IPC) and pharmacological preconditioning (PPC) protect cardiac myocytes against reversible and irreversible injury and the genesis of cardiac arrhythmias1 in all animal species and humans, the effect of IPC and PPC on endothelial dysfunction has been less thoroughly studied. In this regard, the first article to clearly establish tha...