Role of voltage-gated proton channel (Hv1) in cancer biology

Abstract

The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.

N-terminal region is responsible for mHv1 channel activity in MDSCs

“…We conclude that, in MDSCs, the alternative splicing of the Hvcn1 gene leads to the modulation of the mHv1 function by directly modulating the extension of the N-terminal beginning (Figure 5), which is tightly coupled to the gating of mHv1 channels, where the shortest isoform exhibits the most advantageous gating and the longest isoform exhibits the least advantageous gating (Figure 5). Given that mHv1.1 expression appears to be dominant and that mHv1.1 exhibits the most efficient gating phenotype among mHv1 diversity, it would be interesting to explore in more detail molecules that are able to interact and induce changes in the function of mHv1.1, such as Hv1 classic activators (i.e., arachidonic acid) (Kawanabe and Okamura 2016), but more significantly, inhibitors (i.e., zinc ion and guanidine ion) (Alvear-Arias et al, 2022, Alvear-Arias et al, 2023, and genetic approaches directed to diminish the levels of mRNAs that translate as mHv1.1, such as siRNA or CRISPR-Cas. mHv1.1 could potentially not only be used as a biomarker, but more Frontiers in Pharmacology frontiersin.org promisingly, also as a therapeutic target in MDSC, with the aim to alleviate immunosuppression in cancer contexts.…”

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

“…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. , …”

“… 11 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. 15 , 16 Voltage sensitivity is conferred by the S4 segment, which contains three positively charged arginine residues, Arg205, Arg208, and Arg211. 2 , 12 , 17 , 18 Upon membrane depolarization, these amino acid residues move outward, resulting in channel opening and proton conduction.…”