REVIEW ■ : Chloride Channel Myotonias

Abstract

Myotonia (muscle stiffness) is a symptom of several inherited diseases in humans and also in animals. It is due to muscle membrane hyperexcitability, which, in turn, can be caused by mutations in plasma membrane ion channels. The skeletal muscle chloride channel CLC-1 provides the major part of muscle membrane conductance and is important for keeping this membrane close to its resting voltage. Mutations in CLC-1 can cause both recessive (Becker) and dominant (Thomsen) forms of myotonia. Some of these mutations have been introduced into the functional cDNA and analyzed in the Xenopus oocyte expression system. From these studies, it was concluded that CLC-1 functions as a homooligomer with probably four subunits. Dominant mutant subunits are assumed to associate with wild-type ones, leading to their inactivation. The principle disease-causing mechanism of dominant mutations is a drastic alteration in the voltage dependence of CLC-1 gating. Some mutations in CLC-1 can be inherited either recessively or dominantly, probably depending on the genetic background. These studies point to the important role of CLC-1 in muscle physiology and provide interesting insights into the structure and function of this gene family of voltage-gated chloride channels. NEUROSCIENTIST 2:225-232, 1996