Voltage-gated proton channel HV1 inhibitors: mode of action and impact on immune functions

• Forschungsstelle: COST
• Projektnummer: C15.0035
• Projekttitel Englisch: Voltage-gated proton channel HV1 inhibitors: mode of action and impact on immune functions

Schlüsselwörter (Englisch)

ion channels; immunityL; signaling; cancer; cell biology

Forschungsprogramme (Englisch)

COST-Action BM1406 - IONCHAN-IMMUNRESPON: ION CHANnels and IMMUNe RESPONse Toward a global understanding of immune cell physiology And for new therapeutic approaches

Kurzbeschreibung (Englisch)

Immune cells express a unique channel that conducts protons across membranes, the voltage-gated proton channel Hv1 that contributes to both innate and adaptive immunity by sustaining the bactericidal activity of neutrophils and the proliferation of B lymphocytes. Hv1 channels are also required for the maintenance of a physiological pH in the cytosol and in the lumen of phagosomes, a function that is essential for the activity of cytosolic and phagosomal enzymes and for the degradation and proper presentation of the ingested antigens. Given the importance of Hv1 channels for immune cell functions, specific inhibitors of Hv1 channels are highly desirable. In this grant application, we propose to test the impact of genetic and pharmacological disruption of Hv1 channel activity on the functions of innate immune cells and to investigate the mode of action of novel inhibitors identified from a large-scale in-house screen. The identification of specific inhibitors of Hv1 channels will provide new therapeutic approaches for the treatment of inflammatory and malignant diseases associated with excessive neutrophil activation or lymphocyte proliferation.

Weitere Hinweise und Angaben (Englisch)

Full name of research-institution/enterprise: Université de Genève Faculté de médecine Département de physiologie cellulaire et métabolisme

Partner und Internationale Organisationen (Englisch)

AT; HR; CZ; DK; EE; FR; MK; DE; EL; HU; IL; IT; LV; LU; NO; PL; PT; SI;ES; SE; TR; UK

Abstract (Englisch)

Immune cells express a unique channel that conducts protons across membranes, the voltage-gated proton channel Hv1 that contributes to both innate and adaptive immunity by sustaining the bactericidal activity of neutrophils and the proliferation of B lymphocytes. We aim to identify specific Hv1 inhibitors by performing a large scale chemical screen validated by patch clamp recordings of Hv1 currents, and test the effect of these inhibitors on Hv1-dependent functions of immune cells isolated from WT and Hv1-deficient mice. We identified 2 compounds affecting the activity of Hv1 channels whose specificity was confirmed by electrophysiological recordings of Hv1-mediated proton currents. We chemically modified these two compounds and identified two analogues that inhibited Hv1 channels at low micro-molar concentrations in fluorescence and patch clamp assays. These analogues significantly reduced Hv1-dependent ROS production by phagocytic cells, suggesting that they could be used to modulate immune cell functions. The identification of specific inhibitors of Hv1 channels will contribute to a better understanding of gating mechanisms of voltage-gated ion channels and provide new therapeutic approaches for the treatment of inflammatory and malignant diseases associated with excessive neutrophil activation or lymphocyte proliferation.

Datenbankreferenzen (Englisch)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C15.0035