A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel

Christoph Fahlke, Carol L. Beck, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl- channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl- channel (hClC- 1) expressed in a mammalian cell line (tsA201). The G230E mutation causes substantial changes in anion and cation selectivity as well as a fundamental change in rectification of the current-voltage relationship. Whereas wild- type channels are characterized by pronounced inward rectification and a Cl > thiocyanate > Br > NO3 > I > CH3SO3 selectivity, G230E exhibits outward rectification at positive potentials and a thiocyanate > NO3 > I > Br > Cl > CH3SO3 selectivity. Furthermore, the cation-to-anion permeability ratio of the mutant is much greater than that of the wild-type channel. Voltage- dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway. Both binding sites are preserved in the mutant but have decreased affinities for iodide. These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore.

Original languageEnglish (US)
Pages (from-to)2729-2734
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number6
DOIs
StatePublished - Mar 18 1997

Keywords

  • CLCN1
  • electrophysiology
  • permeation
  • skeletal muscle

ASJC Scopus subject areas

  • General

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