title: The role of protons in fast and slow gating of the Torpedo chloride channel ClC-0.
abstract: Transmembrane proton transport is of fundamental importance for life. The list of H(+) transporting proteins has been recently expanded with the discovery that some members of the CLC gene family are stoichiometrically coupled Cl(-)/H(+) antiporters. Other CLC proteins are instead passive Cl(-) selective anion channels. The gating of these CLC channels is, however, strongly regulated by pH, likely reflecting the evolutionary relationship with CLC Cl(-)/H(+) antiporters. The role of protons in the gating of the model Torpedo channel ClC-0 is best understood. ClC-0 is a homodimer with separate pores in each subunit. Each protopore can be opened and closed independently from the other pore by a "fast gate". A common, slow gate acts on both pores simultaneously. The opening of the fast gate is controlled by a critical glutamate (E166), whose protonation state determines the fast gate's pH dependence. Extracellular protons likely can arrive directly at E166. In contrast, protonation of E166 from the inside has been proposed to be mediated by the dissociation of an intrapore water molecule. The OH(-) anion resulting from the water dissociation is stabilized in one of the anion binding sites of the channel, competing with intracellular Cl(-) ions. The pH dependence of the slow gate is less well understood. It has been shown that proton translocation drives irreversible gating transitions associated with the slow gate. However, the relationship of the fast gate's pH dependence on the proton translocation and the molecular basis of the slow gate remain to be discovered.
authors.affiliation: Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via De Marini 6, Genoa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zifarelli
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D007477:Ions; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D011522:Protons; D014101:Torpedo / Q000235:genetics / Q000378:metabolism*
chemical_list: D018118:Chloride Channels; D007477:Ions; D011522:Protons