Chloride conductance in mouse muscle is subject to post‐transcriptional compensation of the functional Cl− channel 1 gene dosage

Abstract

In mature mammalian muscle, the muscular chloride channel ClC‐1 contributes about 75% of the sarcolemmal resting conductance (G_m). In mice carrying two defective alleles of the corresponding Clc1 gene, chloride conductance (G_Cl) is reduced to less than 10% of that of wild‐type, and this causes hyperexcitability, the salient feature of the disease myotonia. Potassium conductance (G_K) values in myotonic mouse muscle fibres are lowered by about 60% compared with wild‐type. The defective Clc^adr allele causes loss of the 4.5 kb ClC‐1 mRNA. Mice heterozygous for the defective Clc1^adr allele contain about 50% functional mRNA in their muscles compared with homozygous wild‐type mice. Despite a halved functional gene dosage, heterozygous muscles display an average G_Cl which is not significantly different from that of homozygous wild‐type animals. The G_K values in heterozygotes are also indistinguishable from homozygous wild‐type animals. These results indicate that a regulatory mechanism acting at the post‐transcriptional level limits the density of ClC‐1 channels. G_K is probably indirectly regulated by muscle activity.