Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism.

K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively.

Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome.

Activating mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 and SUR1 are a common cause of neonatal diabetes. Here, we analyse the molecular mechanism of action of the heterozygous mutation F132L, which lies in the first set of transmembrane helices (TMD0) of SUR1.

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes.

ATP-sensitive potassium (K(ATP)) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.

ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic beta-cells.

ATP-sensitive K(+) channels (K(ATP) channels) couple cell metabolism to electrical activity and thereby to physiological processes such as hormone secretion, muscle contraction, and neuronal activity. However, the mechanism by which metabolism regulates K(ATP) channel activity, and the channel sensitivity to inhibition by ATP in its native environment, remain controversial. Here, we used alpha-toxin to permeabilize single pancreatic beta-cells and measure K(ATP) channel ATP sensitivity.

Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects.

Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K(+) channel (K(ATP) channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems.