The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia.
Single-channel recordings of the currents mediated by the muscle Cl- channel, ClC-1, expressed in Xenopus oocytes, provide the first direct evidence that this channel has two equidistant open conductance levels like the Torpedo ClC-0 prototype. As for the case of ClC-0, the probabilities and dwell times of the closed and conducting states are consistent with the presence of two independently gated pathways with approximately 1.2 pS conductance enabled in parallel via a common gate. However, the voltage dependence of the common gate is different and the kinetics are much faster than for ClC-0. Estimates of single-channel parameters from the analysis of macroscopic current fluctuations agree with those from single-channel recordings. Fluctuation analysis was used to characterize changes in the apparent double-gate behavior of the ClC-1 mutations I290M and I556N causing, respectively, a dominant and a recessive form of myotonia. We find that both mutations reduce about equally the open probability of single protopores and that mutation I290M 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. Differential 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.
Istituto di Cibernetica e Biofisica, CNR, I-16149 Genova, Italy.
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D000465:Algorithms; D000818:Animals; D018118:Chloride Channels / Q000235:genetics* / Q000648:ultrastructure*; D004594:Electrophysiology; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics* / Q000648:ultrastructure*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009222:Myotonia / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D014982:Xenopus laevis
C086321:CLC-1 channel; D018118:Chloride Channels; D009124:Muscle Proteins