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Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic beta-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59-->Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.

Original publication

DOI

10.1126/science.1186146

Type

Journal article

Journal

Science

Publication Date

23/07/2010

Volume

329

Pages

458 - 461

Keywords

ATP-Binding Cassette Transporters, Adenosine Triphosphate, Animals, Ataxia, Diabetes Mellitus, Female, Gene Targeting, Humans, Infant, Newborn, Male, Membrane Potentials, Mice, Mice, Transgenic, Motor Activity, Muscle Hypotonia, Muscle Strength, Muscles, Neurons, Patch-Clamp Techniques, Postural Balance, Potassium Channels, Inwardly Rectifying, Purkinje Cells, Receptors, Drug, Sulfonylurea Receptors, Syndrome