Comment on ion transit pathways and gating in ClC chloride channels.

ClC chloride channels possess a homodimeric structure in which each monomer contains an independent chloride ion pathway. ClC channel gating is regulated by chloride ion concentration, pH and voltage. Based on structural and physiological evidence, it has been proposed that a glutamate residue on the extracellular end of the selectivity filter acts as a fast gate. We utilized a new search algorithm that incorporates electrostatic information to explore the ion transit pathways through wild-type and mutant bacterial ClC channels. Examination of the chloride ion permeation pathways supports the importance of the glutamate residue in gating. An external chloride binding site previously postulated in physiological experiments is located near a conserved basic residue adjacent to the gate. In addition, access pathways are found for proton migration to the gate, enabling pH control at hyperpolarized membrane potentials. A chloride ion in the selectivity filter is required for the pH-dependent gating mechanism.