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Microglial Voltage-Gated Proton Channel Hv1 in Neurological Disorders
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Madhuvika Murugan, Long-Jun Wu
Voltage-gated proton currents have been observed in immune cells and were believed to be a component of NOX (DeCoursey 2003). However, the discovery of Hv1 proton channel demonstrated that voltage-gated proton current is mediated by its own ion channel. In 2006, two independent groups reported that the HVCN1 gene encodes an ion channel with voltage-dependent, proton selective flux (Ramsey et al. 2006, Sasaki, Takagi, and Okamura 2006). By comparing the sequence homology to the voltage sensor domain of voltage-gated cation channels, the gene HVCN1 encoding the voltage-gated proton channel from human genome was identified by the Clapham lab and named proton channel Hv1 to denote the first member in the family. Concurrently, Okamura lab used a similar strategy and identified mouse voltage-gated proton channel, mVSOP (mouse voltage-sensor domain-only protein) (Sasaki, Takagi, and Okamura 2006). It is notable that mVSOP is a homologue of the voltage-sensitive lipid phosphatase found in Ciona intestinalis (Murata et al. 2005). The Hv1 channel was later identified in coccolithophores (Taylor et al. 2011) and dinoflagellate (Smith et al. 2011). In addition, genes that are homologous to HVCN1 are present in many species, from green alga, zebrafish, to monkey (DeCoursey 2013).
Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy
Published in OncoImmunology, 2022
Flor Navarro, Noelia Casares, Celia Martín-Otal, Aritz Lasarte-Cía, Marta Gorraiz, Patricia Sarrión, Diana Llopiz, David Reparaz, Nerea Varo, Juan Roberto Rodriguez-Madoz, Felipe Prosper, Sandra Hervás-Stubbs, Teresa Lozano, Juan José Lasarte
They include the family of carbonic anhydrases(CAs),14 the vacuolar-typeH+-ATPaseprotonpump,15 anion exchangers such as AE1(SLC4A1)16 and AE2(SLC4A2),17Na+/HCO3− co-transporterssuch asSLC4A4,18 and theNa+/H+ exchanger 1 NHE1(SLC9A1).19 Among the SLC4 family of HCO3 – transporters, theNa+-independentCl–/HCO3 – anion exchanger 2 (AE2, SLC4A2) is considered a master acid loader in many celltypes.20,21 Under physiological conditions, AE2 favors the extrusion of intracellularHCO3− in exchange for extracellularCl−, resulting in an acid load. Previous studies showed that mice carrying a targeted deletion of Ae2(Ae2a,b–/ – mice) have lymphocytes with abnormalpHivalues, which eventually leads to an abnormal state of T cell activation andautoimmunity.22–24 We also found that AE2 inhibition with a synthetic peptide improved effector T cell functions in vitro.25 These data prompted us to investigate the role of the pH acidifier AE2 as a potential target for tumor immunotherapy. On the other hand, the voltage-gatedH+ channel (Hv1) encoded by the Hvcn1 gene is a highly selectiveH+ extruder that avoids cell acidification anddepolarization.26 Hv1 can restore cytoplasmic pH in seconds after heavy acid loads in different cell types including neurons, neutrophils, macrophages, and epithelial cells, amongothers.27–30 Moreover, in breast and colorectal cancers, Hv1 expression was correlated with worse prognosis, and the pharmacological inhibition of Hv1 caused the acidification of the tumor cellpHiand consequently decreased tumor proliferation andmigration.13,31 Hv1 was also shown to be necessary to regulate thepHiof Jurkatcells.12 In this scenario, we hypothesized that overexpression of Hv1 or AE2 silencing in T cells could facilitate the alkalinization of theirpHieven in the acidic TME and accordingly enhance the antitumor activity. These genetic modifications could be of interest in adoptive T cell therapies based on T cell receptor (TCR) transgenic T cells or in chimeric antigen receptor expressing T cells (CAR T cells).