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Voltage changes across the cell membrane control the gating of many cation-selective ion channels. Conserved from bacteria to humans1, the voltage-gated-ligand superfamily of ion channels are encoded as polypeptide chains of six transmembrane-spanning segments (S1-S6). S1-S4 functions as a self-contained voltage-sensing domain (VSD), in essence a positively charged lever that moves in response to voltage changes. The VSD 'ligand' transmits force via a linker to the S5-S6 pore domain 'receptor'2, thereby opening or closing the channel. The ascidian VSD protein Ci-VSP gates a phosphatase activity rather than a channel pore, indicating that VSDs function independently of ion channels3. Here we describe a mammalian VSD protein (HV1) that lacks a discernible pore domain but is sufficient for expression of a voltage-sensitive proton-selective ion channel activity. Hv1 currents are activated at depolarizing voltages, sensitive to the transmembrane pH gradient, H+-selective, and Zn2+-sensitive. Mutagenesis of Hv1 identified three arginine residues in S4 that regulate channel gating and two histidine residues that are required for extracellular inhibition of Hv1 by Zn2+. Hv1 is expressed in immune tissues and manifests the characteristic properties of native proton conductances (GvH+). In phagocytic leukocytes4, GvH+are required to support the oxidative burst that underlies microbial killing by the innate immune system4,5. The data presented here identify Hv1 as a long-sought voltage-gated H+channel and establish Hv1 as the founding member of a family of mammalian VSD proteins.