PubMed 20022885

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kir6.2

Title: Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms.

Authors: Roope Männikkö, Craig Jefferies, Sarah E Flanagan, Andrew Hattersley, Sian Ellard, Frances M Ashcroft

Journal, date & volume: Hum. Mol. Genet., 2010 Mar 15 , 19, 963-72

PubMed link:

ATP-sensitive potassium (K(ATP)) channels regulate insulin secretion from pancreatic beta-cells. Gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause neonatal diabetes. We report two novel mutations on the same haplotype (cis), F60Y and V64L, in the slide helix of Kir6.2 in a patient with neonatal diabetes, developmental delay and epilepsy. Functional analysis revealed the F60Y mutation increases the intrinsic channel open probability (Po(0)), thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell K(ATP) currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same (but not a different) subunit. These data indicate that F60Y is the pathogenic mutation and reveal that interactions between slide helix residues can influence K(ATP) channel gating.