Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin.

Journal article

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.

Authors: Clark, R; McTaggart, J; Webster, R; Mannikko, R; Iberl, M

• Publication status: Published
• Journal: Science (New York, N.Y.)
• Volume: 329
• Issue: 5990
• Pages: 458-461
• Publication date: 2010-07-01
• DOI: 10.1126/science.1186146
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English
• Keywords: Male; Syndrome; Postural Balance; Muscles; Membrane Potentials; Mice; Ataxia; Mice, Transgenic; Neurons; Muscle Hypotonia; Motor Activity; Female; Infant, Newborn; Sulfonylurea Receptors; Purkinje Cells; Potassium Channels, Inwardly Rectifying; Animals; Adenosine Triphosphate; Receptors, Drug; Muscle Strength; Gene Targeting; ATP-Binding Cassette Transporters; Patch-Clamp Techniques; Humans; Diabetes Mellitus