{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Voltage‐gated proton channels encoded by HVCN1 mediate a highly selective proton conductance that is tightly regulated by both membrane potential and the transmembrane pH gradient."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " This channel plays a central role in diverse physiological processes. In phagocytic cells, HVCN1 is essential for compensating the charge imbalance that arises during NADPH oxidase–mediated reactive oxygen species (ROS) production, thereby sustaining the respiratory burst."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In B lymphocytes, HVCN1 associates with the B‐cell receptor complex to modulate ROS‐dependent signaling, which in turn affects kinase activation, metabolic responses, and antibody production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In human spermatozoa, the channel is densely localized along the flagellum where its voltage‐ and pH‐dependent gating facilitates proton extrusion, leading to intracellular alkalinization that is required for sperm activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " HVCN1 also contributes to pH regulation in epithelial cells, as it mediates apical acid secretion in airways to help maintain airway surface liquid pH."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of disease, aberrant expression and genetic alterations of HVCN1 have been implicated in cancer progression. For example, enhanced HVCN1 expression correlates with increased invasiveness and poor prognosis in metastatic breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while specific mutations in HVCN1 in follicular lymphoma are associated with improved progression‐free survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies further reveal that HVCN1 assembles as a dimer with cooperative gating behavior, with key residues and internal water molecules constituting a “water wire” that underlies its remarkable proton selectivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these findings position HVCN1 as a multifaceted regulator that integrates ion transport with redox signaling, immune activation, reproductive competence, and tumor pathophysiology, highlighting its potential as a therapeutic target in a variety of clinical contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mari Sasaki, Masahiro Takagi, Yasushi Okamura "}, {"type": "b", "children": [{"type": "t", "text": "A voltage sensor-domain protein is a voltage-gated proton channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1122352"}], "href": "https://doi.org/10.1126/science.1122352"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16556803"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16556803"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "I Scott Ramsey, Evelyne Ruchti, J Stefan Kaczmarek, et al. 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