title: Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin.
abstract: 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.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Clark
authors.forename: James S
authors.initials: JS
authors.lastname: McTaggart
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.forename: Roope
authors.initials: R
authors.lastname: Mannikko
authors.forename: Michaela
authors.initials: M
authors.lastname: Iberl
authors.forename: Xiu Li
authors.initials: XL
authors.lastname: Sim
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Maike
authors.initials: M
authors.lastname: Glitsch
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001259:Ataxia / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009123:Muscle Hypotonia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D053580:Muscle Strength; D009132:Muscles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D004856:Postural Balance; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism*; D011689:Purkinje Cells / Q000502:physiology; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D013577:Syndrome; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel