Different fast-gate regulation by external Cl^- and H⁺ of the muscle-type ClC chloride channels

The fast gate of the muscle-type ClC channels (ClC-0 and ClC-1) opens in response to the change of membrane potential (V). This gating process is intimately associated with the binding of external Cl^- to the channel pore in a way that the occupancy of Cl^- on the binding site increases the channel's open probability (P_o). External H⁺ also enhances the fast-gate opening in these channels, prompting a hypothesis that protonation of the binding site may increase the Cl^- binding affinity, and this is possibly the underlying mechanism for the H⁺ modulation. However, Cl^- and H^-, modulate the fast-gate P_o-V curve in different ways. Varying the external Cl^- concentrations ([Cl^-]_o) shifts the P_o-V curve in parallel along the voltage axis, whereas reducing external pH mainly increases the minimal P_o of the curve. Furthermore, H⁺ modulations at saturating and nonsaturating [Cl^-]_o are similar. Thus, the H⁺ effect on the fast gating appears not to be a consequence of an increase in the Cl^- binding affinity. We previously found that a hyperpolarization-favored opening process is important to determine the fastgate P_o of ClC-0 at very negative voltages. This [Cl^-]_o-independent mechanism attracted little attention, but it appears to be the opening process that is modulated by external H⁺.