The Pore of the Voltage-Gated Proton Channel

SummaryIn classical tetrameric voltage-gated ion channels four voltage-sensing domains (VSDs), one from each subunit, control one ion permeation pathway formed by four pore domains. The human Hv1 proton channel has a different architecture, containing a VSD, but lacking a pore domain. Since its location is not known, we searched for the Hv permeation pathway. We find that mutation of the S4 segment's third arginine R211 (R3) compromises proton selectivity, enabling conduction of a metal cation and even of the large organic cation guanidinium, reminiscent of Shaker's omega pore. In the open state, R3 appears to interact with an aspartate (D112) that is situated in the middle of S1 and is unique to Hv channels. The double mutation of both residues further compromises cation selectivity. We propose that membrane depolarization reversibly positions R3 next to D112 in the transmembrane VSD to form the ion selectivity filter in the channel's open conformation.

► R3 in the S4 of the hHv1 proton channel is part of its cation selectivity filter ► Mutation of R3 allows conduction of Gu+, as seen in K+ and Na+ channel omega pores ► D112 in S1 interacts with R3 in the open channel and contributes to selectivity ► Thus, gating of hHv1 involves the formation of its selectivity filter