Exotic properties of a voltage-gated proton channel from the snail Helisoma trivolvis .

Voltage-gated proton channels, HV 1, were first reported in Helix aspersa snail neurons. These H+ channels open very rapidly, two to three orders of magnitude faster than mammalian HV 1. Here we identify an HV 1 gene in the snail Helisoma trivolvis and verify protein level expression by Western blotting of H. trivolvis brain lysate. Expressed in mammalian cells, HtHV 1 currents in most respects resemble those described in other snails, including rapid activation, 476 times faster than hHV 1 (human) at pHo 7, between 50 and 90 mV. In contrast to most HV 1, activation of HtHV 1 is exponential, suggesting first-order kinetics. However, the large gating charge of ∼5.5 e 0 suggests that HtHV 1 functions as a dimer, evidently with highly cooperative gating. HtHV 1 opening is exquisitely sensitive to pHo , whereas closing is nearly independent of pHo Zn2+ and Cd2+ inhibit HtHV 1 currents in the micromolar range, slowing activation, shifting the proton conductance-voltage ( g H - V ) relationship to more positive potentials, and lowering the maximum conductance. This is consistent with HtHV 1 possessing three of the four amino acids that coordinate Zn2+ in mammalian HV 1. All known HV 1 exhibit ΔpH-dependent gating that results in a 40-mV shift of the g H - V relationship for a unit change in either pHo or pHi This property is crucial for all the functions of HV 1 in many species and numerous human cells. The HtHV 1 channel exhibits normal or supernormal pHo dependence, but weak pHi dependence. Under favorable conditions, this might result in the HtHV 1 channel conducting inward currents and perhaps mediating a proton action potential. The anomalous ΔpH-dependent gating of HtHV 1 channels suggests a structural basis for this important property, which is further explored in this issue (Cherny et al. 2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201711968).