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  • The acidification of endocytic compartments is closely relat

    2024-07-09

    The acidification of endocytic compartments is closely related to endocytic activity, although the mechanism linking acidification and membrane dynamics is largely unknown. In a recent RNA interference (RNAi)-based screen, V-ATPase depletion blocked the formation of clathrin-coated vesicles, an effect that was rescued by adding exogenous cholesterol [22]; moreover, the time course of cholesterol depletion from the plasma membrane was correlated with the formation of coated vesicles. Cells treated with bafilomycin for >24h exhibited complete loss of transferrin internalization, showing that the V-ATPase activity is required for the early stage of receptor-mediated endocytosis [22]. These observations suggest that V-ATPase participates in the endocytosis by maintaining cholesterol distribution through recycling the membrane lipids from endosomes back to the plasma membrane. However, the V-ATPase knockout phenotype—induced either genetically or pharmacologically—differs from those of omecamtiv with impaired luminal acidification. Cells expressing V-ATPase mutants or treated with V-ATPase-specific inhibitors, still internalize proteins to early endosomes [23], [24], suggesting that acute omecamtiv inhibition of V-ATPase is not sufficient to block early steps in endocytosis. Nevertheless, endocytosis plays a regulatory role in multiple signaling pathways, in both positive and negative fashions. A large body of evidence reveals that the signaling is regulated at different levels and cellular locations along the endocytic route, as well as at the cell surface [25]. Thus, endocytic defects resulting from V-ATPase deficiency may result in aberrant signal transduction. However, V-ATPase may be more directly involved in the regulation and function of signal transduction. We now describe several key findings that support this possibility and discuss the implications for cellular and tissue physiology.
    Summary
    Transparency document
    Acknowledgments This research was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Individual Research Grants in Doshisha Women's College of Liberal Arts (No.14-8) to GHSW.
    Introduction The brain integrates divergent inputs from far and near to control most functions of the body directly or indirectly. The excitable property of the neurons is critically responsible for instantaneous as well as optimum functioning of the brain. The enzyme Na-K ATPase plays a pivotal role in maintaining neuronal transmembrane potential gradient and excitability (Larsen et al., 2016). Several behaviours and factors affect the Na-K ATPase activity and thus, modulate the brain excitability (Kaphzan et al., 2013; Lingrel et al., 2007; McCarren and Alger, 1987). Under normal condition rapid eye movement sleep (REMS), an essential cognitive state, maintains brain excitability by modulating the Na-K ATPase activity (Gulyani and Mallick, 1993; Mallick et al., 1999). Consistent studies showed that the REMS maintains brain level of noradrenaline (NA), which modulates the brain Na-K ATPase activity and brain excitability (Khanday et al., 2016; Mallick et al., 2000; Mallick and Adya, 1999). These findings led us to propose that normally REMS maintains brain excitability and thus, serves house-keeping function of the brain (Mallick and Singh, 2011). The Na-K ATPase actively exchanges Na+/K+ across the plasma membrane in all mammalian cells, including the neurons and is responsible for maintenance of transmembrane electrical potential gradient. It plays a critical role in executing normal neuronal activity and function (Mobasheri et al., 2000). The Na-K ATPase is a transmembrane tetrameric protein consisting two each of α- and β-subunits. The α-subunit is responsible for the catalytic and transport properties of the enzyme, while the β- is regulatory subunit. Both, the α- and β-subunits of Na-K ATPase exist in multiple isoforms, which are encoded by different genes and follow developmental as well as tissue specific expression patterns (Lingrel et al., 2003; Orlowski and Lingrel, 1988; Sweadner, 1989). Although α1-, α3- and β1-subunits are usually expressed in all neuronal cells (Juhaszova and Blaustein, 1997), α2-isoform has been reported to be expressed by some neuronal cells only (Moseley et al., 2007). The existence of isoforms with varying kinetic properties and expression patterns suggests their specific role.