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

The fast gate of the muscle-type CIC channels (CIC-0 and CIC-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- oil 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-], are similar. Thus, the H+ effect oil 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 fast-gate P-o of CIC-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+.