Voltage-Gated Proton Channels in the Tree of Life

Abstract

With a single gene encoding HV1 channel, proton channel diversity is particularly low in mammals compared to other members of the superfamily of voltage-gated ion channels. Nonetheless, mammalian HV1 channels are expressed in many different tissues and cell types where they exert various functions. In the first part of this review, we regard novel aspects of the functional expression of HV1 channels in mammals by differentially comparing their involvement in (1) close conjunction with the NADPH oxidase complex responsible for the respiratory burst of phagocytes, and (2) in respiratory burst independent functions such as pH homeostasis or acid extrusion. In the second part, we dissect expression of HV channels within the eukaryotic tree of life, revealing the immense diversity of the channel in other phylae, such as mollusks or dinoflagellates, where several genes encoding HV channels can be found within a single species. In the last part, a comprehensive overview of the biophysical properties of a set of twenty different HV channels characterized electrophysiologically, from Mammalia to unicellular protists, is given.

The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair

“…These interactions exert a strong effect on gating, particularly on the stability of the open state [ 158 , 159 ]. Hv1 channels are expressed on the plasma membrane and phagosomes and are widely distributed in many different tissues and cell types [ 160 , 161 ]. Hv1 channels are mainly expressed in immune cells such as neutrophils, macrophages, B-lymphocytes, and T-lymphocytes, and play an important role in the immune system [ 161 - 165 ].…”

Identification of a Novel Structural Class of HV1 Inhibitors by Structure-Based Virtual Screening

“…The structure of H V 1 consists only of a voltage-sensing domain (VSD) that contains four transmembrane segments (S1–S4). The S5–S6 pore-forming domain found in other voltage-gated ion channels is absent in H V 1, resulting in the proton-selective permeation pathway being located within the S1–S4 transmembrane segments . In most species, the channel operates as a homodimer, and each monomer has its own voltage sensor, pH sensor, and proton permeation pathway and can function independently. , Voltage sensitivity is conferred by the S4 segment, which contains three positively charged arginine residues, Arg205, Arg208, and Arg211. ,,, Upon membrane depolarization, these amino acid residues move outward, resulting in channel opening and proton conduction. ,, In voltage-gated proton channels, only the open or closed states can be distinguished; there is no inactivation mechanism. , …”

“…Voltage-gated proton channel 1 (H V 1) is a transmembrane protein that was first described more than 30 years ago, however, the channel gene ( hvcn1, hydrogen voltage-gated channel 1) was not identified until 2006. − H V 1 is expressed in various immune cells, skeletal muscle cells, oocytes, osteoclasts, blood cells, sperm cells and DRG neurons. ,− H V 1 channels are exclusively selective for protons, conducted through the voltage sensing domain (VSD), in which aspartate and arginine residues are responsible for the high proton selectivity. ,,, Moreover, these channels can detect changes in membrane potential and open their conduction pathway as a result of membrane depolarization and subsequent conformational changes …”

“…H V 1 channels are involved in many signaling pathways, and their most important role is the regulation of the intracellular pH. , They normally conduct an outward current of H + ions, driven by their electrochemical gradient . By controlling cytoplasmic pH, they are involved in many biological functions, such as the immune response and proliferation, motility and capacitation of human spermatozoa .…”

Maxwell’s True Current

“…'Protons' in biology. It is easy for physicists and engineers to be confused by the use of the word 'proton' in biology [32][33][34]. The word 'proton' in the relevant biological literature is shorthand for positively charged water, which can take on many chemical forms [35][36][37][38] depending on the chemical and biological context, for example, depending on the structure of the proteins it moves through.…”