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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
The voltage-gated proton channel, Hv1, is a unique ion channel with high selectivity for protons. The proton extrusion through the channel is gated via voltage- and pH-dependent mechanisms. The Hv1 channel is mainly expressed in immune cells such as macrophages, neutrophils, and eosinophils (Ramsey et al. 2006, Sasaki, Takagi, and Okamura 2006). As the primary immune cells in the central nervous system (CNS), microglia are known to highly express the Hv1 channel. Voltage-gated proton currents were characterized in culture microglia many years ago (Eder and DeCoursey 2001), but its molecular identity as the voltage-gated proton channel Hv1 was only recently elucidated (Ramsey et al. 2006, Sasaki, Takagi, and Okamura 2006). Indeed, Hv1 is selectively and functionally expressed in microglia but not neurons in the mouse brain (Wu et al. 2012, Wu 2014a). Microglial Hv1 regulates intracellular pH and promotes nicotinamide adenine dinucleotide phosphate oxidase (NOX)-dependent generation of reactive oxygen species (ROS). In a mouse model of middle cerebral artery occlusion (MCAO), Hv1 knockout (KO) mice were protected from ischemic damage, showing reduced NOX-dependent ROS production, microglia activation and neuronal cell death (Wu et al. 2012, Wu 2014b, Tian et al. 2016). A similar neuroprotective phenotype was noted in experimental models of spinal cord injury (SCI) and multiple sclerosis (MS), wherein, Hv1 KO mice exhibited white matter sparing and improved motor recovery compared to the wild-type (WT) mice (Liu et al. 2015, Murugan et al. 2020, Li et al. 2020, Li et al. 2021). Interestingly, functional Hv1 expression was also identified in human glioblastoma multiforme (GBM), the most common and lethal brain tumor with possible implications in cancer metastasis (Ribeiro-Silva et al. 2016, Fernandez et al. 2016, Bare et al. 2020). These studies illuminate a critical role for Hv1, particularly microglial Hv1 in neurological disorders, providing a strong rationale for targeting Hv1 for therapeutic benefit. This chapter provides a comprehensive overview of our current understanding of microglial Hv1 in normal and pathological states, and recent progress in the pharmaceutical development of small molecules for Hv1 inhibition.
Participation of signaling proteins in sperm hyperactivation
Published in Systems Biology in Reproductive Medicine, 2022
Joaquín Cordero-Martínez, Guadalupe Elizabeth Jimenez-Gutierrez, Charmina Aguirre-Alvarado, Verónica Alacántara-Farfán, Germán Chamorro-Cevallos, Ana L. Roa-Espitia, Enrique O. Hernández-González, Lorena Rodríguez-Páez
Regulation of the pHi of sperm during capacitation is not exclusively performed by CAs, NBC, AE1, NHE, and CFTR. Another essential channel involved in this task is the voltage-gated proton channel (Hv), which extrudes protons from the cytoplasm to increase the pHi (DeCoursey 2013). In human sperm, Hv is located in the principal piece of the flagellum, regulated by Vm and extracellular pH, and activated by oleic acid (Lishko et al. 2010). Recently, it has been reported that Hv is activated by an increased concentration of albumin, which initiates capacitation and allows the acrosome reaction (Zhao et al. 2021). Hv is colocalized with CatSper and is responsible for controlling flagellar pH and Ca2+ homeostasis, mainly through the activation of CatSper; through their combined action, they can increases the pHi and [Ca2+]i, as required for human sperm hyperactivation (Lishko et al. 2010; Lishko and Kirichok 2010). Hv also contains an N-terminal isoform named Hv1Sper, which is controlled by changes in pH (ΔpH) and the pH itself. Hv1Sper and Hv are assemble as heterodimers and present properties different from those of the homodimers, suggesting an adaptation to ΔpH (Berger et al. 2017). Notably, the Hv current is absent in mouse sperm because the functional vsop gene is not expressed (Lishko and Kirichok 2010), therefore, the KO mouse model is fertile (Ramsey et al. 2009).