The aims of this proposal are directed toward the understanding of the structure and function of the CIC family of voltage-gated chloride channels. Mutations within the gene encoding the CIC-1 channel in human or goat skeletal muscle have been shown by a number of groups, including the applicant's, to result in inherited forms of myotonia congenita. The applicant has also contributed to the analysis of how these mutations affect channel function by characterizing wild-type and mutant channels in transfected HEK293 cells using electrophysiological methods. These naturally occurring mutations have provided a framework on which to generate further mutations by site-directed methods with the aim of mapping channel domains that constitute the voltage sensor and ion pore. In addition, the applicant proposes to delineate the transmembrane topology of the CIC channel using a glycosylation tagging method that has previously been employed to generate a topological model of AMPA-type glutamate receptors.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Physiology Study Section (PHY)
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Lymn, Richard W
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Vanoye, Carlos G; George Jr, Alfred L (2002) Functional characterization of recombinant human ClC-4 chloride channels in cultured mammalian cells. J Physiol 539:373-83
Rogers, Christopher S; Vanoye, Carlos G; Sullenger, Bruce A et al. (2002) Functional repair of a mutant chloride channel using a trans-splicing ribozyme. J Clin Invest 110:1783-9
Bianchi, L; Miller 3rd, D M; George Jr, A L (2001) Expression of a CIC chloride channel in Caenorhabditis elegans gamma-aminobutyric acid-ergic neurons. Neurosci Lett 299:177-80
Fahlke, C; Desai, R R; Gillani, N et al. (2001) Residues lining the inner pore vestibule of human muscle chloride channels. J Biol Chem 276:1759-65
George Jr, A L; Bianchi, L; Link, E M et al. (2001) From stones to bones: the biology of ClC chloride channels. Curr Biol 11:R620-8
Rutledge, E; Bianchi, L; Christensen, M et al. (2001) CLH-3, a ClC-2 anion channel ortholog activated during meiotic maturation in C. elegans oocytes. Curr Biol 11:161-70
Jing, H; Xu, Y; Carson, M et al. (2000) New structural motifs on the chymotrypsin fold and their potential roles in complement factor B. EMBO J 19:164-73
Rhodes, T H; Vite, C H; Giger, U et al. (1999) A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog. FEBS Lett 456:54-8
George Jr, A L (1998) Chloride channels and endocytosis: ClC-5 makes a dent. Proc Natl Acad Sci U S A 95:7843-5