Proton Channels in the Context of Human Diseases

Mustafa Erdem Sağsöz

doi:10.62425/rtpharma.1771654

Proton Channels in the Context of Human Diseases

Abstract

Proton channels play an important role in many physiological processes in humans, as in all organisms, since pH determines protonation or deprotonisation state of amino acid residues, thus channel activity, enzyme kinetics, receptor-ligand interactions by changing the surface charges of molecules. These integral protein structures, which selectively transport protons through biological membranes, are very important for cell homeostasis, energy production and signal transmission. Human diseases linked to proton channels can be effectively studied using genetic model organisms, as the fundamental structure and function of these channels are conserved across species. Proton channels in humans, are an important part of many vital processes, including the regulation of pH in cellular compartments, the generation of bioelectric signals in neurons, and the immune response. Studies about proton channels conducted to date, including deviations in proton channel function have been associated with a variety of diseases, from neurodegenerative disorders to cardiovascular diseases and cancer. Valuable information about their special contributions to human physiology and pathophysiology can be obtained by deciphering their different roles in these structures. The aim of this review is to provide a comprehensive overview of the biological significance of proton channels by summarizing their functions and their effects on organisms, with particular emphasis on their roles in human diseases and their potential as therapeutic targets. An integrative synthesis connecting molecular mechanisms to disease-specific pathophysiology is still lacking. This review aims to address this gap by providing a comprehensive overview of the biological significance of proton channels.

Keywords

References

Alvear‐Arias, J. J., Pena-Pichicoi, A., Carrillo, C., Fernandez, M., Gonzalez, T., Garate, J. A., & Gonzalez, C. (2023). Role of voltage-gated proton channel (Hv1) in cancer biology. Frontiers in Pharmacology, 14, 1175702. https://doi.org/10.3389/fphar.2023.1175702
Bayrhuber, M., Maslennikov, I., Kwiatkowski, W., Sobol, A., Wierschem, C., Eichmann, C., Frey, L., & Riek, R. (2019). Nuclear Magnetic Resonance Solution Structure and Functional Behavior of the Human Proton Channel. Biochemistry, 58(39), 4017–4027. https://doi.org/10.1021/acs.biochem.9b00471
Bushman, J. D., Ye, W., & Liman, E. R. (2015). A proton current associated with sour taste: distribution and functional properties. FASEB Journal, 29(7), 3014–3026. https://doi.org/10.1096/fj.14-265694
Chaves, G., Bungert-Plümke, S., Franzen, A., Mahorivska, I., & Musset, B. (2020). Zinc modulation of proton currents in a new voltage-gated proton channel suggests a mechanism of inhibition. FEBS Journal, 287(22), 4996–5018. https://doi.org/10.1111/febs.15291
DeCoursey, T. E. (2013). Voltage-gated proton channels: molecular biology, physiology, and pathophysiology of the H(V) family. Physiological Reviews, 93(2), 599–652. https://doi.org/10.1152/physrev.00011.2012
DeCoursey, T. E. (2024). Transcendent aspects of proton channels. Annual Review of Physiology, 86, 357–377. https://doi.org/10.1146/annurev-physiol-042222-023242
El Chemaly, A., Jaquet, V., Cambet, Y., Caillon, A., Cherpin, O., Balafa, A., Krause, K.-H., & Demaurex, N. (2023). Discovery and validation of new Hv1 proton channel inhibitors with onco-therapeutic potential. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1870(3).
Fernández, A., Pupo, A., Mena-Ulecia, K., & Gonzalez, C. (2016). Pharmacological modulation of proton channel Hv1 in cancer therapy: Future perspectives. Molecular Pharmacology, 90(3), 385–402. https://doi.org/10.1124/mol.116.103804

Ganguly, A., Chandel, A., Turner, H., Wang, S., Liman, E. R., & Montell, C. (2021). Requirement for an Otopetrin-like protein for acid taste in Drosophila. Proceedings of the National Academy of Sciences, 118(51). https://doi.org/10.1073/pnas.2110641118
Kuwabara, M. F., Klemptner, J., Muth, J., De Martino, E., Oliver, D., & Berger, T. K. (2024). Zinc inhibits the voltage-gated proton channel HCNL1. Biophysical Journal, 123(24), 4256–4265. https://doi.org/10.1016/j.bpj.2024.08.018
Lishko, P. V., Botchkina, I. L., Fedorenko, A., & Kirichok, Y. (2010). Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel. Cell, 140, 327–337.
Lim, V. T., Freites, J. A., Tombola, F., & Tobias, D. J. (2021). Thermodynamics and Mechanism of the Membrane Permeation of Hv1 Channel Blockers. The Journal of membrane biology, 254(1), 5–16. https://doi.org/10.1007/s00232-020-00149-8
Liu, T., Liang, L., Zhao, P., Lin, W., Zhuang, Y., Jiang, L., Chen, H., & Li, C. (2024). The M2 Protein of the Influenza A Virus Interacts with PEX19 to Facilitate Virus Replication by Disrupting the Function of Peroxisome. Viruses, 16(8), 1309. https://doi.org/10.3390/v16081309
Lopez, I. A., Ishiyama, G., Acuna, D., & Ishiyama, A. (2019). Otopetrin-2 immunolocalization in the human macula utricle. Annals of Otology, Rhinology & Laryngology, 128(6_suppl), 96S–102S. https://doi.org/10.1177/0003489419834952
Mishra, A. K., Kumar, A., Yadav, S., Anand, M., Yadav, B., Nigam, R., Garg, S. K., & Swain, D. K. (2019). Functional insights into voltage-gated proton channel (Hv1) in bull spermatozoa. Theriogenology, 136, 118–130.
Musset, B., Clark, R. A., DeCoursey, T. E., Petheo, G. L., Geiszt, M., Chen, Y., Cornell, J. E., Eddy, C. A., Brzyski, R. G., & Jamali, A. E. (2012). NOX5 in human spermatozoa: expression, function, and regulation. Journal of Biological Chemistry, 287, 9376–9388.
Nakhaei, P., Hiscott, J., & Lin, R. (2010). STING-ing the antiviral pathway. Journal of Molecular Cell Biology, 2(3), 110–112. https://doi.org/10.1093/jmcb/mjp048
Neal, M. L., Beier, E. E., Hossain, M. M., Boyle, A., Zheng, J., Kim, C., Mhatre-Winters, I., Wu, L. J., & Richardson, J. R. (2023). Voltage-Gated Proton Channel Hv1 Regulates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson's Disease Models. Antioxidants (Basel, Switzerland), 12(3), 582. https://doi.org/10.3390/antiox12030582
Okochi, Y., & Okamura, Y. (2021). Regulation of neutrophil functions by Hv1/VSOP voltage-gated proton channels. International Journal of Molecular Sciences, 22, 2620.
Ozbil, M. (2019). Computational investigation of influenza A virus M2 protein inhibition mechanism by ion channel blockers. Turkish Journal of Chemistry, 43(1), 235–245. https://doi.org/10.3906/kim-1805-39
Palmer, B. F., Kelepouris, E., & Clegg, D. J. (2021). Renal tubular acidosis and management strategies: a narrative review. Advances in Therapy, 38(2), 949–968. https://doi.org/10.1007/s12325-020-01587-5
Pang, H., Li, J., Du, H., Gao, Y., Lv, J., Liu, Y., & Li, S. J. (2020). Loss of voltage-gated proton channel Hv1 leads to diet-induced obesity in mice. BMJ Open Diabetes Research & Care, 8, e000951. https://doi.org/10.1136/bmjdrc-2019-000951
Pankratova, Y., McKay, M. J., Ma, C., Tan, H., Wang, J., & Hong, M. (2024). Structure and dynamics of the proton-selective histidine and the gating tryptophan in an inward-rectifying hybrid influenza B and A virus M2 proton channel. Physical Chemistry Chemical Physics, 26(30), 20629–20644. https://doi.org/10.1039/d4cp01648c
Ramsey, I. S., Moran, M. M., Chong, J. A., & Clapham, D. E. (2006). A voltage-gated proton-selective channel lacking the pore domain. Nature, 440, 1213–1216. https://doi.org/10.1038/nature04700
Sağsöz, M. E., Sağlam, B., Arslan, K., Baştuğ, T., Çavuş, M., & Puralı, N. (2024). Structural, functional and molecular dynamics examination of a de novo cloned Otopetrin-like proton channel in crayfish. Cell Biochemistry and Biophysics. Advance online publication. https://doi.org/10.1007/s12013-024-01310-z
Saotome, K., Teng, B., Tsui, C. C. A., Lee, W. H., Tu, Y. H., Kaplan, J. P., Sansom, M. S. P., Liman, E. R., & Ward, A. B. (2019). Structures of the otopetrin proton channels Otop1 and Otop3. Nature Structural & Molecular Biology, 26(6), 518–525. https://doi.org/10.1038/s41594-019-0236-6 .
Takeshita, K., Sakata, S., Yamashita, E., Fujiwara, Y., Kawanabe, A., Kurokawa, T., Okochi, Y., Matsuda, M., Narita, H., Okamura, Y., & Nakagawa, A. (2014). X-ray crystal structure of voltage-gated proton channel. Nature Structural & Molecular Biology, 21, 352–357. https://doi.org/10.1038/nsmb.2795
Tian-le, X., & Wu, L.-J. (Eds.). (2021). Nonclassical Ion Channels in the Nervous System (1st ed.). CRC Press. https://doi.org/10.1201/9781003109266
Tu, Y. H., Cooper, A. J., Teng, B., Chang, R. B., Artiga, D. J., Turner, H. N., Mulhall, E. M., Ye, W., Smith, A. D., & Liman, E. R. (2018). An evolutionarily conserved gene family encodes proton-selective ion channels. Science, 359(6379), 1047–1050. https://doi.org/10.1126/science.aao4090
Qu, H., Su, Y., Yu, L., Zhao, H. and Xin, C. (2019), Wild-type p53 regulates OTOP2 transcription through DNA loop alteration of the promoter in colorectal cancer. FEBS Open Bio, 9: 26-34. https://doi.org/10.1002/2211-5463.12554
Vavřina Z., Gutten O., Smola M, Zavřel, M., Tehrani, Z. A., Charvát, V., Kožíšek, M., Boura, E., Birkuš, G., & Rulíšek, L. (2021). Protein–Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory. Biochemistry, 60, 607-620.
Walker J. E. (2013). The ATP synthase: the understood, the uncertain and the unknown. Biochemical Society transactions, 41(1), 1–16. https://doi.org/10.1042/BST20110773
Wang, G. X., Cho, K. W., Uhm, M., Hu, C. R., Li, S., Cozacov, Z., Xu, A. E., Cheng, J. X., Saltiel, A. R., Lumeng, C. N., Lin, J. D. (2014). Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation. Diabetes, 63, 1340–1352.
Wobig, L., Wolfenstetter, T., Fechner, S., Bönigk, W., Körschen, H. G., Jikeli, J. F., Trötschel, C., Feederle, R., Kaupp, U. B., & Seifert, T. K. (2020). A family of hyperpolarization-activated channels selective for protons. Proceedings of the National Academy of Sciences of the United States of America, 117(24), 13783–13791. https://doi.org/10.1073/pnas.2001214117
Yue Z, Wu J, Teng D, Wang Z, Voth GA. (2024). Activation of the influenza B M2 proton channel (BM2). bioRxiv. Published online July 26. doi:10.1101/2024.07.26.605324
Zhang, H., You, Q.-D., & Xu, X.-L. (2020). Targeting Stimulator of Interferon Genes (STING): A Medicinal Chemistry Perspective. Journal of Medicinal Chemistry, 63(8),3785–3816. https://doi.org/10.1021/acs.jmedchem.9b01039
Zheng, J., Murugan, M., Wang, L., & Wu, L. J. (2022). Microglial voltage-gated proton channel Hv1 in spinal cord injury. Neural Regeneration Research, 17(6), 1183–1189. https://doi.org/10.4103/1673-5374.327315

Details

Primary Language

English

Subjects

Medical Biotechnology (Other)

Journal Section

Review Article

Authors

Mustafa Erdem Sağsöz ^*
0000-0002-3324-6942
Türkiye

Early Pub Date

October 8, 2025

Publication Date

January 15, 2026

Submission Date

August 25, 2025

Acceptance Date

October 7, 2025

Published in Issue

Year 2025 Volume: 3 Number: 3

DOI

https://doi.org/10.62425/rtpharma.1771654

IZ

https://izlik.org/JA59WM36YF

Cite

RIS / Bibtex

APA

Sağsöz, M. E. (2026). Proton Channels in the Context of Human Diseases. Recent Trends in Pharmacology, 3(3), 104-109. https://doi.org/10.62425/rtpharma.1771654

AMA

1.Sağsöz ME. Proton Channels in the Context of Human Diseases. Recent Trends in Pharmacology. 2026;3(3):104-109. doi:10.62425/rtpharma.1771654

Chicago

Sağsöz, Mustafa Erdem. 2026. “Proton Channels in the Context of Human Diseases”. Recent Trends in Pharmacology 3 (3): 104-9. https://doi.org/10.62425/rtpharma.1771654.

EndNote

Sağsöz ME (January 1, 2026) Proton Channels in the Context of Human Diseases. Recent Trends in Pharmacology 3 3 104–109.

IEEE

[1]M. E. Sağsöz, “Proton Channels in the Context of Human Diseases”, Recent Trends in Pharmacology, vol. 3, no. 3, pp. 104–109, Jan. 2026, doi: 10.62425/rtpharma.1771654.

ISNAD

Sağsöz, Mustafa Erdem. “Proton Channels in the Context of Human Diseases”. Recent Trends in Pharmacology 3/3 (January 1, 2026): 104-109. https://doi.org/10.62425/rtpharma.1771654.

JAMA

1.Sağsöz ME. Proton Channels in the Context of Human Diseases. Recent Trends in Pharmacology. 2026;3:104–109.

MLA

Sağsöz, Mustafa Erdem. “Proton Channels in the Context of Human Diseases”. Recent Trends in Pharmacology, vol. 3, no. 3, Jan. 2026, pp. 104-9, doi:10.62425/rtpharma.1771654.

Vancouver

1.Mustafa Erdem Sağsöz. Proton Channels in the Context of Human Diseases. Recent Trends in Pharmacology. 2026 Jan. 1;3(3):104-9. doi:10.62425/rtpharma.1771654