Relaxing messages from the sarcolemma

593 C o m m e n t a r y In spite of the detailed understanding reached in the last 50 years about the molecular mechanisms of muscle excitability, the localization of the Cl  conductance, G Cl , in muscle has remained highly contended. In this issue, Lueck et al. address this long-standing controversy, measuring directly the Cl  current mediated by the ClC-1 channel using the patch clamp technique and by detailed localization studies in mouse muscle fibers. They convincingly conclude that the vast majority of ClC-1 channels is localized in the surface membrane (sarco-lemma) and not in the T-tubules. This result contrasts with several previous reports and requires a reinterpre-tation of the mechanism by which the Cl  conductance limits T-tubular K + accumulation. Skeletal muscle activity consists of a sequence of excit-atory and relaxatory events. Excitation relies on the propagation of action potentials (APs) from the neuro-muscular junction along the sarcolemma via voltage-dependent Na + channels. A specialized membrane domain, the T-tubule system, is formed by regularly spaced in-vaginations of the sarcolemma in correspondence to the M-lines, allowing the efficient spreading of the AP to the muscle interior. The T-tubular membrane forms tight contacts with the sarcoplasmic reticulum (SR) (" triads "). Here, voltage-gated L-type Ca 2+ channels (di-hydropyridine receptors [DHPRs]) act as voltage sensors that transmit the membrane depolarization to the SR-localized Ca 2+ release channels (ryanodine receptors [RYRs]) to liberate Ca 2+ from the SR, leading finally to muscle contraction. Full and fast repolarization of the membrane potential is critical to allow high frequency neuronal stimulation and to prevent Na + and Ca 2+ channel inactivation. Classically, in neurons, the repolarization of the AP is mediated by delayed rectifier K + channels. In skeletal muscle, in contrast, a large part of the repolarization appears to be mediated by the high background Cl