1.A.51 The Voltage-gated Proton Channel (VPC) Family

Voltage-gated ion channels of the VIC family (1.A.1) consist of four 6 TMS domains. TMSs 1-4 in the 4 subunits or domains constitute the voltage sensor while TMSs 5 and 6 comprise the ion channel (Nelson et al., 1999). Proteins consisting only of the sensor domain (TMSs 1-4) have been identified. Sasaki et al. (2006) identified the mouse RIKEN cDNA 0610039P13 in the GenBank database as such a 4 TMS protein and named it mouse voltage sensor domain-only protein (mVSOP). They showed it is a voltage-gated proton channel. Similarly, Ramsey et al. (2006) identified a human gene called Hv1 as a voltage-gated proton channel. The latter group had previously identified an ascidian voltage-sensing domain homologous to those in VIC family members, that gates (regulates) the associated phosphatase activity rather than a channel activity.  Purified Hv channels, free of all other proteins, by themselves, catalyze H+ fluxes (Lee et al., 2009).  Hv1 most likely forms an internal water wire for selective proton transfer, and interactions between water molecules and S4 arginines may underlie coupling between voltage- and pH-gradient sensing (Ramsey et al. 2010).  It also responds to mechanical stress (Pathak et al. 2016).  The S4 segment of these channels transits between three major conformational states, and only the transitions between the inward and outward conformations are highly dependent on voltage and pH (Han et al. 2022). Arachidonic acid reverses cholesterol and zinc inhibition of human voltage-gated proton channels (Han et al. 2023).

The mouse and human VPC proteins are >90% identical. Hv1 is activated at depolarizing voltages, sensitive to the transmembrane pH gradient, H+-selective, and Zn2+-sensitive. Three arg residues in S4 regulate channel gating, and two his residues are required for extracellular inhibition by Zn2+. Hv1 is present in phagocytic leukocytes and is required for the oxidative burst that underlies microbial killing via the gp91phox phagocyte NADPH oxidase associated cytochrome b558 (CytB) family (TC #1.A.20). This argues against the contested claim that gp91phox is itself (or contains) H+ channel activity. The human voltage gated Hv1 is a homodimer (Lee et al., 2008) with two pores and gates (Tombola et al., 2008). The dimer interface corresponds to the interface between the voltage sensor and pore in Kv channels (Lee et al., 2008; DeCoursey, 2008). The monomer is probably also functional (Koch et al., 2008; Tombola et al., 2008).

Homologues of VPCs are found in ascidians, zebrafish, Xenopus and mammals (Sasaki et al., 2006). While TMSs 2 and 3 contain well-conserved negatively charged residues, TMS4 contains positively charged residues. These charged residues presumably confer upon these transmembrane proteins both their H+ channel activities and their voltage sensor capacities. Of the VIC family members, these proteins show greatest sequence similarity with the voltage sensors of voltage-gated Na+ channels. Because they lack the channel domain (TMSs 5 and 6) of VIC family members, the VPC family is considered distinct from the VIC family. However, it can be considered to be in the VIC superfamily.

Voltage-gated ion channels derive their voltage sensitivity from the movement of specific charged residues in response to a change in transmembrane potential. Several studies on mechanisms of voltage sensing in ion channels support the idea that these gating charges move through a well-defined permeation pathway. This gating pathway in a voltage-gated ion channel can also be mutated to transport free cations, including protons (Chanda and Bezanilla, 2008). The discovery of proton channels homologous to voltage-sensing domains suggests that the same gating pathway is used by voltage-dependent proton transporters.

The Hv1 channel of humans (1.A.51.1.2) contains a voltage-sensing domain (VSD), similar to those of voltage-gated sodium, potassium and calcium channels. The pore domain of these other channels, which forms a central pore at the interface of the four subunits, is missing in Hv1. Tombola et al. 2009 review efforts to understand the structural organization of Hv1 channels. They discuss the relationship between the gating of Hv1 and the gating of ion-conducting pores recently discovered in the VSDs of mutant voltage-gated potassium and sodium channels.  Flagellar Hv1-dependent proton conductance in human sperm is activated by membrane depolarization, an alkaline extracellular environment, endocannabinoid anandamide, and removal of extracellular zinc, a potent Hv1 blocker. Hv1 allows only outward transport of protons and is therefore dedicated to inducing intracellular alkalinization and activating spermatozoa (Lishko et al. 2010).

Voltage-gated proton channels are designed to extrude large quantities of cytosolic acid in response to depolarising voltages. The discovery of the Hvcn1 gene and the generation of mice lacking the channel molecule have confirmed several postulated functions of proton channels in leukocytes. In neutrophils and macrophages, proton channels are required for high-level production of superoxide anions by the phagocytic NADPH oxidase, a bactericidal enzyme essential for host defence against infections. In B lymphocytes, proton channels are required for low-level production of superoxide that boosts the production of antibodies. Proton channels sustain the activity of immune cells in several ways. By extruding excess cytosolic acid, proton channels prevent deleterious acidification of the cytosol and at the same time deliver protons required for chemical conversion of the superoxide secreted by membrane oxidases. By moving positive charges across membranes, proton channels limit the depolarisation of the plasma membrane, promoting the electrogenic activity of NADPH oxidases and the entry of calcium ions into cells. Acid extrusion by proton channels is not restricted to leukocytes but also mediates the intracellular alkalinisation required for the activation of spermatozoids. Proton channels are therefore multitalented channels that control male fertility as well as our innate and adaptive immunity (Demaurex & El Chemaly et al., 2010).

Voltage-gated proton (Hv) channels play an essential role in phagocytic cells by generating a hyperpolarizing proton current that electrically compensates for the depolarizing current generated by the NADPH oxidase during the respiratory burst, thereby ensuring a sustained production of reactive oxygen species by the NADPH oxidase in phagocytes to neutralize engulfed bacteria. Neutralizations of three charged residues in the fourth transmembrane domain, S4, reduce the voltage dependence of activation (Gonzalez et al. 2013). The middle S4 charged residue moves from a position accessible from the cytosolic solution to a position accessible from the extracellular solution, suggesting that this residue moves across most of the membrane electric field during voltage activation. The charge movement of these three S4 charges accounts for almost all of the measured gating charge in Hv channels (Gonzalez et al. 2013). 

Hv assembles as a dimeric channel, and the two transmembrane channel domains function cooperatively, mediated by the coiled-coil assembly domain in the cytoplasmic C terminus. A picture of the dimer configuration based on the analyses of interactions among the two voltage sensor domains (VSDs) and a coiled-coil domain has been presented (Fujiwara et al. 2014). The two S4 helices are probably situated closely in the dimeric channel. Continuous helices stretching from the transmembrane to the cytoplasmic region in the dimeric interface may regulate channel activation in the Hv dimer.  The voltage sensing domain (VSD) of the voltage-gated proton channel, Hv1, mediates a H+-selective conductance that is coordinately controlled by the membrane potential (V) and the transmembrane pH gradient (ΔpH) (Villalba-Galea 2014). Allosteric control of Hv1 channel opening by ΔpH (V-ΔpH coupling) is manifested by a characteristic shift of approximately 40 mV per ΔpH unit in the activation. To understand the mechanism for V-ΔpH coupling in Hv1, H+ current kinetics of activation and deactivation in excised membrane patches were analyzed as a function of the membrane potential and the pH in the intracellular side of the membrane (pHI) (Villalba-Galea 2014). Opening of the Hv1 channel is preceded by a voltage-independent transition. For Hv1, the VSD functions as both the voltage sensor and the conduction pathway, suggesting that the voltage independent transition is intrinsic to the voltage-sensing domain. 

The voltage-gated proton channel Hv1 plays a critical role in the fast proton translocation that underlies a wide range of physiological functions, including the phagocytic respiratory burst, sperm motility, apoptosis, and metastatic cancer. Both voltage activation and proton conduction are carried out by a voltage-sensing domain (VSD) with strong similarity to canonical VSDs in voltage- dependent cation channels and enzymes (Li et al. 2015).

Hv1 is a dimer of two voltage-sensing domains (VSDs), each containing a pore pathway, a voltage sensor (S4), and a gate (S1), forming its own ion channel (Mony et al. 2020). Opening of the two channels in the dimer is cooperative. Part of the cooperativity is due to association between coiled-coil domains that extend intracellularly from the S4s. Interactions between the transmembrane portions of the subunits may also contribute. Using functional analysis of a mutagenesis scan, biochemistry, and modeling, Mony et al. 2020 found that the subunits form a dimer interface along the entire length of S1, and also have intersubunit contacts between S1 and S4. These interactions exert a strong effect on gating, in particular on the stability of the open state. These results suggest that gating in Hv1 is tuned by extensive VSD-VSD interactions between the gates and voltage sensors of the dimeric channel.

The generalized transport reaction catalyzed by members of the VPC family is:

H+ (in) → H+ (out)

This family belongs to the VIC Superfamily.



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TC#NameOrganismal TypeExample

The voltage-gated proton channel, mVSOP (269 aas and 2 TMSs) (Sasaki et al., 2006).  A hydrophobic plug functions as the gate (Chamberlin et al. 2013). Gating current measurements revealed that voltage-sensor (VS) activation and proton-selective aqueous conductance opening are thermodynamically distinct steps in the Hv1 activation pathway and showed that pH changes directly alter VS activation. Gating cooperativity, pH-dependent modulation, and a high degree of H+ selectivity have been demonstrated (De La Rosa and Ramsey 2018).


mVSOP of Mus musculus (Q9DCE4)


The voltage-gated proton channel, Hv1, Hv1, HV1 or HVCN1 (273 aas) (Ramsey et al., 2006). Thr29 is a phosphorylation site that activates the HVCN1 channel in leukocytes (Musset et al., 2010). The condctivity pore has been delineated and depends of a carboxyl group (Asp or Glu) in the channel (Morgan et al. 2013). The four transmembrane helices sense voltage and the pH gradient, and conduct protons exclusively. Selectivity is achieved by the unique ability of H3O+ to protonate an Asp-Arg salt bridge. Pathognomonic sensitivity of gating to the pH gradient ensures HV1 channel opening only when acid extrusion will result, which is crucial to its biological functions (DeCoursey 2015). An exception occurs in dinoflagellates (see 1.A.51.1.4) in which H+ influx through HV1 triggers a bioluminescent flash. The gating mechanism of Hv1, cooperativity within dimers and the sensitivity to metal ions have been reviewed (Okamura et al. 2015). How this channel is activated by cytoplasmic [H+] and depolarization of the membrane potential has been proposed by Castillo et al. 2015. The extracellular ends of the first transmembrane segments form the intersubunit interface that mediates coupling between binding sites, while the coiled-coil domain does not directly participate in the process (Hong et al. 2015). Deep water penetration through hHv1 has been observed, suggesting a highly focused electric field, comprising two helical turns along the fourth TMS. This region likely contains the H+ selectivity filter and the conduction pore. A 3D model offers an explicit mechanism for voltage activation based on a one-click sliding helix conformational rearrangement (Li et al. 2015).  Trp-207 enables four characteristic properties: slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and ΔpH-dependent gating (Cherny et al. 2015).  The native Hv structure is a homodimer, with the two channel subunits functioning cooperatively (Okuda et al. 2016).  Segment S3 plays a role in activating gating (Sakata et al. 2016).  Two sites have been identified: one is the binding pocket of 2GBI (accessible to ligands from the intracellular side); the other is located at the exit site of the proton permeation pathway (Gianti et al. 2016).   Crystal structures of Hv1 dimeric channels revealed that the primary contacts between the two monomers are in the C-terminal domain (CTD), which forms a coiled-coil structure. Molecular dynamics (MD) simulations of full-length and truncated CTD models revealed a strong contribution of the CTD to the packing of the TMSs (Boonamnaj and Sompornpisut 2018).  Histidine-168 is essential for the ΔpH-dependent gating (Cherny et al. 2018). Proton transfer in Hv1 utilizes a water wire, and does not require transient protonation of a conserved aspartate in the S1 transmembrane helix (Bennett and Ramsey 2017).  Hv1 channels are present in bull spermatozoa, and these regulate sperm functions like hypermotility, capacitation and acrosome reaction through a complex interplay between different pathways involving cAMP, PKC, and Catsper (Mishra et al. 2019). A zinc binding site influences gating configurations of HV1 (Cherny et al. 2020). The discovery and validation of Hv1 proton channel inhibitors with onco-therapeutic potential have been described (El Chemaly et al. 2023). Nitrates can stimulate the biosynthesis of hydrophilic yellow pigments (HYPs) in Monascus ruber (Huang et al. 2023). ATP influences Hv1 activity via direct molecular interactions, and its functional characteristics are required for the physiological activity of Hv1 (Kawanabe et al. 2023).


Hv1 of Homo sapiens (Q96D96)


Voltage-gated proton channel, HvCN1; VSOP; VSX1 (Sasaki et al., 2006).  Exhibits voltage and pH-dependent gating as well as Zn2+-reactivity. In the dimeric strcuture, each subumit has a proton channel. TMS4 appears to be the voltage sensor.  Subunit cooperativity has been demonstrated (Gonzalez et al. 2010).




HvCN1 of Ciona intestinalis (Q1JV40)


Voltage-gated proton-specific monomeric channel, kHv1. Activated by depolarization; functions in signaling and excitability to trigger bioluminescence (Smith et al., 2011).  Hv1 most likely forms an internal water wire for selective proton transfer, and interactions between water molecules and S4 arginines may underlie coupling between voltage- and pH-gradient sensing (Ramsey et al. 2010).


kHv1 of Karlodinium veneficum (G5CPN9)


Proton channel protein, NpHv1 of 239 aas and 4 TMSs.  Proton selectivity, and pH- and voltage-dependent gating have been demoonstrated. Mutations in the first transmembrane segment at position 66 (Asp66), the presumed selectivity filter, led to a loss of proton-selective conduction (Chaves et al. 2016).

NpHv1 of Nicoletia phytophila


Hv1 proton channel of 223 aas and 4 TMSs. It's proton transport activity has been demonstrated (Zhao and Tombola 2021).

Hv1 of Suillus luteus


Proton channel protein of 211 aas and 4 TMSs. It's proton channel activity has been demonstrated and shown to differ in its regulation from the fungal channel with TC# 1.A..51.1.6 (Zhao and Tombola 2021). The presence of protein sequences corresponding to such channels were demonstrated in all four types of fungi (Zhao and Tombola 2021).

Hv1 of Aspergillus oryzae


TC#NameOrganismal TypeExample

The voltage-sensor containing phosphatase, VSP, of 576 aas and 4 TMSs N-terminal to the phosphatase domain. The enzyme region of VSP contains the phosphatase and C2 domains, is structurally similar to the tumor suppressor phosphatase PTEN, and catalyzes the dephosphorylation of phosphoinositides. The transmembrane voltage sensor is connected to the phosphatase through a short linker region, and phosphatase activity is induced upon membrane depolarization (Zhang et al. 2018). The coupling between the two domains has been studied (Sakata et al. 2017). Membrane depolarization activates the phosphatase activity of the enzyme, presumably via electroconformational coupling between the sensor domain and the enzyme (Sanders and Hutchison 2018). Both the phosphatase domain and the C2 domain move with similar timing upon membrane depolarization (Sakata and Okamura 2018). Four states are visited sequentially in a stepwise manner during voltage activation, each step translocating one arginine or the equivalent of approximately 1 e0 across the membrane electric field, yielding a transfer of approximately 3 e0 charges in total for the complete process (Shen et al. 2022).


VSP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis)


Voltage-sensing phosphatase-2, VSP2, isoform X1, of 509 aas with 4 N-terminal TMSs that comprise the voltage sensor. 

VSP2 of Xenopus laevis (African clawed frog)


Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase, TPTE2, isoform gamma of522 aas and 4 TMSs.

TPTE2 of Homo sapiens


Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase, PTEN of 403 aas and 1 N-terminal TMS. It acts as a dual-specificity lipid phosphatase and a protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (Li and Sun 1997). It is involved in the regulation of synaptic function in excitatory hippocampal synapses, and is recruited to the postsynaptic membrane upon NMDA receptor activation. It is also required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression. Its expression is not affected by smoking of cigarettes or e-cigarettes (Shabestari et al. 2023).

PTEN of Homo sapiens