MULTIMERIC STRUCTURE OF CLC-1 CHLORIDE CHANNEL REVEALED BY MUTATIONS IN DOMINANT MYOTONIA-CONGENITA (THOMSEN)

Voltage-gated ClC chloride channels play important roles in cell volum e regulation, control of muscle excitability, and probably transepithe lial transport. ClC channels can be functionally expressed without oth er subunits, but it is unknown whether they function as monomers. We n ow exploit the properties of human mutations in the muscle chloride ch annel, ClC-1, to explore its multimeric structure. This is based on an alysis of the dominant negative effects of ClC-1 mutations causing myo tonia congenita (MC, Thomsen's disease), including a newly identified mutation (P480L) in Thomsen's own family. In a co-expression assay, Th omsen's mutation dramatically inhibits normal ClC-1 function. A mutati on found in Canadian MC families (G230E) has a less pronounced dominan t negative effect, which can be explained by functional WT/G230E heter ooligomeric channels with altered kinetics and selectivity. Analysis o f both mutants shows independently that ClC-1 functions as a homeoligo mer with most likely four subunits.