Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Poster Abstracts

7-POS Board 7 DESCRIBING THE BIOPHYSICAL PROPERTIES OF A SUPER-LONG FORM OF THE HUMAN VOLTAGE-GATED PROTON CHANNEL (H V 1 SL ) Karl-Matthäus Herold 1 ; Carolin Jäger 1 ; Chaves Gustavo 1 ; Iryna Mahorivska 1 ; Arne Franzen 2 ; Christian Derst 1 ; Boris Musset 1 ; 1 Paracelsus Medical University , Center of Physiology, Pathophysiology and Biophysics (CPPB) – Nuremberg, Nuremberg, Germany 2 FZ Jülich, Molekular- und Zellphysiologie (IBI-1) , Jülich, Germany The human voltage-gated proton channel hHV1, encoded by the HVCN1 gene on chromosome 12q24.11, is essential for intracellular pH homeostasis and charge compensation during processes such as the respiratory burst in phagocytes. Beyond immune function, hHV1 contributes to sperm maturation, airway epithelial pH regulation, B-cell receptor signaling, and reactive oxygen species production. While generally beneficial, hHV1 activity has been implicated in pathological conditions, including ischemic stroke and cancer progression. Functionally, hHV1 acts as a proton “overpressure valve,” opening in response to intracellular acidification and enabling proton extrusion, thereby increasing intracellular pH. To date, two splice variants have been described: the full-length wild-type (WT, 273 amino acids) and a shorter isoform (hHV1S, 253 amino acids), which lacks part of the N-terminus and enhances proton currents, particularly in B cells and leukemic cells. Using gene structure analysis and transcript predictions (Gnomon), we identified a previously undescribed third isoform, termed hHV1SL (super-long). This variant contains an additional 47 amino acids within the N-terminal region, inserted between residues 7 and 8 of the WT sequence. RT-PCR analyses indicate that hHV1SL is expressed in multiple tumor cell lines, including lymphomas, leukemias, and multiple myelomas. Notably, mRNA expression was also detected in the choroid plexus, suggesting a potential role in the central nervous system. Functional characterization in HEK cells using patch-clamp electrophysiology revealed that hHV1SL is properly targeted to the plasma membrane and forms a proton-selective channel. It is activated by membrane depolarization, modulated by the transmembrane Δ pH gradient, and inhibited by Zn² ⁺ . While activation kinetics resemble those of the WT channel, differences in deactivation kinetics were observed, particularly under inward proton gradients. These findings provide the first functional insights into hHV1SL and establish a foundation for understanding its physiological and pathological relevance.

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