Chloride channels take center stage in a muscular drama

The generation of action potentials in excitable cells requires selective ion channels that open and close upon changes in membrane potential. Initially, cell excitabil-ity was mainly studied in neuronal axons, and in this particular cell compartment, electrical excitability is almost exclusively governed by cation channels. For many years, voltage-dependent anion channels were thought to be of no relevance for cell excitability and considered mere " background " or " leakage " channels involved in housekeeping functions. Skeletal muscle was the first excitable tissue shown to exhibit a significant anion conductance (Hodgkin and Horowicz, 1959). Although the resting muscle chloride conductance largely exceeds the resting potassium conductance, chloride ions do not contribute to the resting membrane potential under physiological conditions. Variations of external [Cl  ] cause only a transient change in membrane potential that results in rapid redistribution of anions and return of the transmembrane voltage to the initial value (Hodgkin and Horowicz, 1959). The physiological role of the muscle chloride conductance was therefore initially unclear. A genetic human disease, myotonia congenita, helped to clarify the impact of muscle chloride channels and provided an example of how background conductances can contribute to the modulation of cell excitability. Patients with myotonia suffer from muscle stiffness that is usually experienced as trouble releasing the grip on objects or as difficulties rising from a sitting position. An animal model of myotonia congenita, the myotonic goat, allowed detailed investigation of the underlying disease mechanisms (Bryant, 1976). Work on muscle preparations of this animal revealed that myotonia con-genita is caused by an overexcitability of the muscle fiber. Myotonic muscle fibers exhibit a decreased resting chloride conductance (Lipicky and Bryant, 1973), and normal muscle fibers can be made hyperexcitable upon block of muscle chloride channels (Bryant and Morales-Aguilera, 1971). In a landmark study on muscle excitability and myotonia, Adrian and Bryant (1974) demonstrated that the existence of transverse tubules, deep invaginations of the sarcolemma that permit the quick penetration of electrical signals to the muscle in-Correspondence to Christoph Fahlke: fahlke.christoph@­mh-hannover.de terior, makes muscle chloride channels necessary for normal muscle excitability. In normal as well as in myo-tonic muscle fibers, a series of action potentials results in extracellular potassium accumulation and depolar-ization of the T-tubules. In normal muscle, a large resting chloride conductance reduces the length constant of electrotonic signal propagation and prevents transmission of T-tubular depolarization to the surface membrane. In myotonic muscle, electrotonic propagation is …