The muscle chloride channel ClC-1 has a double-barreled appearance that isdifferentially affected in dominant and recessive myotonia

Single-channel recordings of the currents mediated by the muscle Cl- channe l, ClC-1, expressed in Xenopus oocytes, provide the first direct evidence t hat this channel has two equidistant open conductance levels like the Torpe do ClC-0 prototype. As for the case of ClC-0, the probabilities and dwell t imes of the closed and conducting states are consistent with the presence o f two independently gated pathways with approximate to 1.2 pS conductance e nabled in parallel via a common gate. However, the voltage dependence of th e common gate is different and the kinetics are much faster than for ClC-0. Estimates of single-channel parameters from the analysis of macroscopic cu rrent fluctuations agree with those from single-channel recordings. Fluctua tion analysis was used to characterize changes in the apparent double-gate behavior of the ClC-1 mutations I290M and I556N causing, respectively, a do minant and a recessive form of myotonia. We find that both mutations reduce about equally die open probability of single protopores and that mutation I2SOM yields a stronger reduction of the common gate open probability than mutation I556N. Our results suggest that the mammalian ClC-homologues have the same structure and mechanism proposed for the Torpedo channel ClC-0. Di fferential effects on the two gates that appear to modulate the activation of ClC-1 channels may be important determinants for the different patterns of inheritance of dominant and recessive ClC-1 mutations.