title: Pharmacology of voltage-gated proton channels.
abstract: Voltage-gated proton channels are highly proton selective ion channels that are present in many cells. Although their unitary conductance is 1000 times smaller than that of most ion channels, detection of single-channel currents supports their identification as channels rather than carriers. Proton channels are gated by membrane depolarization, but their absolute voltage dependence is also strongly regulated by the pH gradient, DeltapH (pHo-pHi). A model of this behavior postulates regulatory protonation sites that are alternately accessible to external or internal solutions. Consequently, proton channels open only when the electrochemical gradient is outward, and serve to extrude acid from cells. No "classical" blockers of proton channels that bind to and physically occlude the channel have been identified. A number of weak bases that inhibit proton currents probably act indirectly, perhaps by changing local pH. The best known and most potent inhibitors are polyvalent cations, especially Zn(2+) and Cd(2+). These cations are coordinated at two or more external protonation sites, most likely His residues where they compete with protons and interfere with gating. In phagocytes, proton channels are required to compensate for the electrogenic action of NADPH oxidase. During the "respiratory burst," i.e., when NADPH oxidase is active, proton channels in these cells adopt an "activated" gating mode. Recently, two labs identified a gene that codes for either the proton channel itself or a protein that is essential for proton channel activity. Expression of this protein results in currents with many similarities to the native channel.
authors: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Harrison, Chicago, IL 60612, USA. tdecours@rush.edu
authors: Thomas E
authors: TE
authors: DeCoursey
authors: Vladimir V
authors: VV
authors: Cherny
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002104:Cadmium / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011522:Protons; D016897:Respiratory Burst; D015032:Zinc / Q000378:metabolism
chemical_list: D007473:Ion Channels; D049990:Membrane Transport Modulators; D011522:Protons; D002104:Cadmium; D019255:NADPH Oxidases; D015032:Zinc