Abstract
Voltage-gated proton channels, H(V)1, were first reported in Helix aspersa snail neurons. These H(+) channels open very rapidly, two to three orders of magnitude faster than mammalian H(V)1. Here we identify an H(V)1 gene in the snail Helisoma trivolvis and verify protein level expression by Western blotting of H. trivolvis brain lysate. Expressed in mammalian cells, HtH(V)1 currents in most respects resemble those described in other snails, including rapid activation, 476 times faster than hH(V)1 (human) at pH(o) 7, between 50 and 90 mV. In contrast to most H(V)1, activation of HtH(V)1 is exponential, suggesting first-order kinetics. However, the large gating charge of ∼5.5 e(0) suggests that HtH(V)1 functions as a dimer, evidently with highly cooperative gating. HtH(V)1 opening is exquisitely sensitive to pH(o), whereas closing is nearly independent of pH(o) Zn(2+) and Cd(2+) inhibit HtH(V)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 HtH(V)1 possessing three of the four amino acids that coordinate Zn(2+) in mammalian H(V)1. All known H(V)1 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(V)1 in many species and numerous human cells. The HtH(V)1 channel exhibits normal or supernormal pH(o) dependence, but weak pH(i) dependence. Under favorable conditions, this might result in the HtH(V)1 channel conducting inward currents and perhaps mediating a proton action potential. The anomalous ΔpH-dependent gating of HtH(V)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).