Gating of the voltage-dependent chloride channel CIC-0 by the permeant anion

CHLORIDE channels of the C1C family are important for the control of membrane excitability1-3, cell volume regulation4–5, and possibly transepithelial transport6,7. Although lacking the typical voltage-sensor found in cation channels8–10, gating of C1C channels is clearly voltage-dependent. For the prototype Torpedo channel CIC-0 (refs 11–15) we now show that channel opening is strongly facilitated by external chloride. Other less permeable anions can substitute for chloride with less efficiency. CIC-0 conductance shows an anomalous mole fraction behaviour with C1~/NO3~ mixtures, suggesting a multi-ion pore. Gating shows a similar anomalous behaviour, tightly linking permeation to gating. Elimi-nating a positive charge at the cytoplasmic end of domain D12 changes kinetics, concentration dependence and halide selectivity of gating, and alters pore properties such as ion selectivity, single-channel conductance and rectification. Taken together, our results strongly suggest that in these channels voltage-dependent gating is conferred by the permeating ion itself, acting as the gating charge.

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