Unexpected Expansion of the Voltage-Gated Proton CHannel Family

Voltage-gated ion channels, whose first identified function was to generate action potentials, are divided into subfamilies with numerous members. The family of voltage-gated proton channels (HV ) is tiny. To date, all species found to express HV , have exclusively one gene that codes for this unique ion channel. Here we report the discovery and characterization of three proton channel genes in the classical model system of neural plasticity, Aplysia californica. The three channels (AcHV1, AcHV2, AcHV3) are distributed throughout the whole animal. Patch-clamp analysis confirmed proton selectivity of these channels but they all differed markedly in gating. AcHV1 gating resembled HV in mammalian channels where it is responsible for proton extrusion and charge compensation. AcHV2 activates more negatively and conducts extensive inward proton current, properties likely to acidify the cytosol. AcHV3, which differs from AcHV1 and AcHV2 in lacking the first arginine in the S4 helix, exhibits proton selective leak currents and weak voltage dependence. We report the expansion of the proton channel family, demonstrating for the first time the expression of three functionally distinct proton channels in a single species.