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

Voltage-gated proton channels, H1, were first reported in snail neurons. These H channels open very rapidly, two to three orders of magnitude faster than mammalian H1. Here we identify an H1 gene in the snail and verify protein level expression by Western blotting of brain lysate. Expressed in mammalian cells, HtH1 currents in most respects resemble those described in other snails, including rapid activation, 476 times faster than hH1 (human) at pH 7, between 50 and 90 mV. In contrast to most H1, activation of HtH1 is exponential, suggesting first-order kinetics. However, the large gating charge of ∼5.5 suggests that HtH1 functions as a dimer, evidently with highly cooperative gating. HtH1 opening is exquisitely sensitive to pH, whereas closing is nearly independent of pH Zn and Cd inhibit HtH1 currents in the micromolar range, slowing activation, shifting the proton conductance-voltage (-) relationship to more positive potentials, and lowering the maximum conductance. This is consistent with HtH1 possessing three of the four amino acids that coordinate Zn in mammalian H1. All known H1 exhibit ΔpH-dependent gating that results in a 40-mV shift of the - relationship for a unit change in either pH or pH This property is crucial for all the functions of H1 in many species and numerous human cells. The HtH1 channel exhibits normal or supernormal pH dependence, but weak pH dependence. Under favorable conditions, this might result in the HtH1 channel conducting inward currents and perhaps mediating a proton action potential. The anomalous ΔpH-dependent gating of HtH1 channels suggests a structural basis for this important property, which is further explored in this issue (Cherny et al. 2018. https://doi.org/10.1085/jgp.201711968).