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

Voltage-gated proton channels, H_V1, were first reported in Helix aspersa snail neurons. These H⁺ channels open very rapidly, two to three orders of magnitude faster than mammalian H_V1. Here we identify an H_V1 gene in the snail Helisoma trivolvis and verify protein level expression by Western blotting of H. trivolvis brain lysate. Expressed in mammalian cells, HtH_V1 currents in most respects resemble those described in other snails, including rapid activation, 476 times faster than hH_V1 (human) at pH_o 7, between 50 and 90 mV. In contrast to most H_V1, activation of HtH_V1 is exponential, suggesting first-order kinetics. However, the large gating charge of ∼5.5 e₀ suggests that HtH_V1 functions as a dimer, evidently with highly cooperative gating. HtH_V1 opening is exquisitely sensitive to pH_o, whereas closing is nearly independent of pH_o Zn²⁺ and Cd²⁺ inhibit HtH_V1 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 HtH_V1 possessing three of the four amino acids that coordinate Zn²⁺ in mammalian H_V1. All known H_V1 exhibit ΔpH-dependent gating that results in a 40-mV shift of the g_H-V relationship for a unit change in either pH_o or pH_i This property is crucial for all the functions of H_V1 in many species and numerous human cells. The HtH_V1 channel exhibits normal or supernormal pH_o dependence, but weak pH_i dependence. Under favorable conditions, this might result in the HtH_V1 channel conducting inward currents and perhaps mediating a proton action potential. The anomalous ΔpH-dependent gating of HtH_V1 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).