An Electrophysiological Comparison of Voltage‐Gated Proton Channels, Other Ion Channels, and Other Proton Channels

Abstract

Abstract. Voltage-gated proton selective channels occupy an ill-defined region between "normal" ion channels and a variety of proton-conducting pathways inside proteins, including, but not limited to, membrane-bound proteins. Voltage-gated H+ channels closely resemble other voltage-gated ion channels in their voltage-and time-dependent gating, but differ in their extreme selectivity, their miniscule singlechannel conductance, and the high activation enthalpy for conduction. Furthermore, in contrast with the "multiple occupancy" hypothesized to account for aspects of permeation through other ion channels, it seems unlikely that H' channels can be occupied by more than one proton at a time. Voltage-gated H+ channels functionally resemble other proton-conducting pathways in proteins, but until their structure has been determined, this similarity will remain speculative. The present restriction to functional measurements is less of a handicap than might be expected-the history of ion channel research shows that deductions based on electrophysiological measurements often closely predict the eventually determined structure. Existing evidence supports the idea that protons permeate the membrane through voltage-gated H+ channels by hopping across a hydrogen-bonded chain that consists of at least some amino acid side groups in addition to water molecules.

Pharmacology of Voltage-Gated Proton Channels

“…Two labs have identified a gene that, when expressed, produces currents that exhibit the main properties of voltage-gated proton currents. The absence of an aqueous channel appears to confirm predictions made over the past decade that the voltage-gated proton channel has a distinct conduction mechanism, a hydrogen-bonded chain (HBC) that includes at least one titratable amino acid side group [1,3,4,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Sasaki and colleagues [22] called the analogous protein in mouse and Ciona intestinalis a VSOP (voltage sensor only protein), because it has the equivalent of the first four membrane-spanning regions (S1-S4) found in most ordinary voltage-gated K + , Na + , or Ca 2+ channels, including the highly charged S4 region that is believed to be the voltage sensor of both conventional channels [23] and proton channels [7,22].…”

“…Although their unitary conductance is 1000 times smaller than that of most ion channels, detection of single-channel currents supports their identification as channels rather than carriers. The absence of an aqueous channel appears to confirm predictions made over the past decade that the voltage-gated proton channel has a distinct conduction mechanism, a hydrogen-bonded chain (HBC) that includes at least one titratable amino acid side group [1,3,4,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. A model of this behavior postulates regulatory protonation sites that are alternately accessible to external or internal solutions.…”

Expression of Hypoxia-Inducible Cell-Surface Transmembrane Carbonic Anhydrases in Human Cancer

“…6,7 Tight control of pH homeostasis in tumors is achieved by using proton extrusion mechanisms that include plasma membrane proton pumps, 29,30 proton channels/proton wires, 31 sodium/proton exchangers, 32 and monocarboxylic acid transporters. 33 Some mechanisms involved in proton extrusion and maintenance of pH homeostasis in and around tumor cells are depicted in Figure 8.…”

Molecular Modeling of the Short-Side-Chain Perfluorosulfonic Acid Membrane

“…oxides, 16 phosphates, 17 sulfates 18 ) transmembrane proteins [19][20][21] (i.e. proton channels 22 and pumps 23 ), carbon nanotubes, 24 and PEMs. [25][26][27][28][29][30][31][32] Clearly, an understanding of both the common (i.e.…”