title: A novel alteration of muscle chloride channel gating in myotonia levior.
abstract: Mutations in the voltage-dependent skeletal muscle chloride channel, ClC-1, result in dominant or recessive myotonia congenita. The Q552R mutation causes a variant of dominant myotonia with a milder phenotype, myotonia levior. To characterise the functional properties of this mutation, homodimeric mutant and heterodimeric wild-type (WT) mutant channels were expressed in tsA201 cells and studied using the whole-cell recording technique. Q552R ClC-1 mutants formed functional channels with normal ion conduction but altered gating properties. Mutant channels were activated by membrane depolarisation, with a voltage dependence of activation that was shifted by more than +90 mV compared to WT channels. Q552R channels were also activated by hyperpolarisation, and this process was dependent upon the intracellular chloride concentration ([Cl(-)](i)). Together, these alterations resulted in a substantial reduction in the open probability at -85 mV at a physiological [Cl(-)](i). Heterodimeric WT-Q552R channels did not exhibit hyperpolarisation-activated gating transitions. As was the case for WT channels, activation occurred upon depolarisation, but the activation curve was shifted by 28 mV to more positive potentials. The functional properties of heterodimeric channels suggest a weakly dominant effect, a finding that correlates with the inheritance pattern and symptom profile of myotonia levior.
authors.affiliation: Department of General Physiology, University of Ulm, 89069 Ulm, Germany.
authors.forename: Aisling
authors.initials: A
authors.lastname: Ryan
authors.forename: Reinhardt
authors.initials: R
authors.lastname: Rüdel
authors.forename: Maya
authors.initials: M
authors.lastname: Kuchenbecker
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
mesh_terms: D000465:Algorithms; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D004594:Electrophysiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D009222:Myotonia / Q000235:genetics / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D014162:Transfection
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels