Functional studies of the ATP-sensitive potassium channel.

KATP channels play key roles in many cell types by coupling the metabolic state of the cell to its electrical activity. Gain-of-function mutations in the KATP channel subunits Kir6.2 and SUR1 cause human neonatal diabetes (ND). In some patients diabetes is permanent, but in others it is transient. A few patients also experience neurological symptoms. The overall goals of this research programme are to understand the relationship between KATP channel structure and function, and to elucidate its role in human neonatal diabetes. We will use an integrated multidisciplinary approach that encompasses studies at the protein, cell and organism level. Electrophysiology of heterologously expressed channels will be used to elucidate the relationship between KATP channel structure and function, focussing how gating is regulated by ligands such as nucleotides and drugs, and how this is affected by ND mutations. Mouse models will be used to investigate how ND mutations lead to diabetes, and t o address questions raised in humans studies. These include: why patients on sulphonylurea therapy respond better to oral glucose than intravenous glucose; why some patients have neonatal diabetes that remits early in life but relapses later; and why some mutations produce neurological symptoms in addition to diabetes.