title: Utrophin regulates modal gating of mechanosensitive ion channels in dystrophic skeletal muscle.
abstract: Dystrophin is a large, submembrane cytoskeletal protein, absence of which causes Duchenne muscular dystrophy. Utrophin is a dystrophin homologue found in both muscle and brain whose physiological function is unknown. Recordings of single-channel activity were made from membrane patches on skeletal muscle from mdx, mdx/utrn(+/-) heterozygotes and mdx/utrn(-/-) double knockout mice to investigate the role of these cytoskeletal proteins in mechanosensitive (MS) channel gating. We find complex, gene dose-dependent effects of utrophin depletion in dystrophin-deficient mdx muscle: (1) increased MS channel open probability, (2) a shift of MS channel gating to larger pressures, (3) appearance of modal gating of MS channels and small conductance channels and (4) expression of large conductance MS channels. We suggest a physical model in which utrophin acts as a scaffolding protein that stabilizes lipid microdomains and clusters MS channel subunits. Depletion of utrophin disrupts domain composition in a manner that favours open channel area expansion, as well as allowing diffusion and aggregation of additional MS channel subunits.
authors.affiliation: Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143-0450, USA.
authors.forename: Nhi
authors.initials: N
authors.lastname: Tan
authors.affiliation: Department of Cellular and Molecular Pharmacology, School of Medicine, University of California, San Francisco, San Francisco, CA, 94143-0450, USA jeff.lansman@ucsf.edu.
authors.forename: Jeffry B
authors.initials: JB
authors.lastname: Lansman
mesh_terms: D000200:Action Potentials; D000818:Animals; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism* / Q000502:physiology; D040542:Mechanotransduction, Cellular; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D049411:Utrophin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; C483600:Utrn protein, mouse; D049411:Utrophin