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The extracellular space normally occupies about one quarter of the total brain volume, but it decreases down to 12C17% during over-excitation by repetitive stimulation or even down to 5% upon ischemia by redistribution of water between the extracellular and intracellular space leading to swelling of neurons and astrocytes (Nicholson, 2005; Sykov, 2004)

Thursday, May 27th, 2021

The extracellular space normally occupies about one quarter of the total brain volume, but it decreases down to 12C17% during over-excitation by repetitive stimulation or even down to 5% upon ischemia by redistribution of water between the extracellular and intracellular space leading to swelling of neurons and astrocytes (Nicholson, 2005; Sykov, 2004). and TRPM7. The Part 1 focuses on the roles of the volume-sensitive outwardly rectifying anion channels (VSOR), also called the volume-regulated anion channel (VRAC), which is activated by cell swelling or reactive oxygen species (ROS) in a manner dependent on intracellular ATP. First we describe phenotypical properties, the molecular identity, and physical pore dimensions of VSOR/VRAC. Second, we highlight the L-Hydroxyproline roles of VSOR/VRAC in the release of organic signaling molecules, such as glutamate, glutathione, ATP and cGAMP, that play ABCC4 roles as double-edged swords in cell survival. Third, we discuss how VSOR/VRAC L-Hydroxyproline is involved in CVR and cell volume dysregulation as well as in the induction of or protection from apoptosis, necrosis and regulated necrosis under pathophysiological conditions. LRRC8D/8E in cisplatin-resistant KCP-4 cells, that are largely deficient in VSOR activity, failed to restore VSOR currents L-Hydroxyproline up to the level in its parental cisplatin-sensitive KB cells (Okada et al., 2017). (3) Different cell types with similar LRRC8 expression levels showed differences in VSOR activities (Okada et al., 2017). (4) The activity of channels reconstituted with LRRC8A LRRC8D/8E was found to be independent of intracellular ATP (Syeda et al., 2016), the fact being at variance with native VSOR activity that is requisitely dependent on intracellular ATP (Jackson et al., 1994; Oiki et al., 1994). (5) Furthermore, the channel reconstituted with purified LRRC8A LRRC8D/8E was not activated by inflation-induced membrane expansion (Syeda et al., 2016), the fact being contradictory to a known fact that VSOR can be activated by pressure-induced cell inflation (Hagiwara et al., 1992; Doroshenko, 1998; Best and Brown, 2009). In place of LRRC8 members, more recently, Tweety homologs (TTYH1, TTYH2, and TTYH3) were proposed as the VSOR core molecules in mouse astrocytes by Han et al. (2019). Subsequently, TTYH1 and TTYH2 were reported to serve as VSOR, in a manner independent of LRRC8A, in human cancer cells including gastric SNU-601, hepatic HepG2 and colonic LoVo cells by Bae et al. (2019). Our data also showed that hypotonicity-induced VSOR currents were significantly suppressed by siRNA-mediated triple knockdown of TTYH1, TTYH2 and TTYH3 in human cervical HeLa cells (Okada et al., 2020), suggesting an involvement of TTYHs in the regulation or formation of VSOR. However, it must be pointed out that studies with making gene knockout and channel reconstitution of TTYH1, TTYH2, and TTYH3 are still missing to firmly support the essential roles of TTYHs in the VSOR/VRAC channel formation. At moment, we need to know as to whether TTYHs can physically interact with LRRC8s and whether the VSOR activity can be restored by overexpression of TTYHs into cells in which all LRRC8s are knocked out. Also, it must be stressed that it is still not definitely determined whether LRRC8 and/or TTYH form the VSOR pore 0.29 nm located at about 1.5 nm from the entrance; then the pore widens up to 1.6 nm around the TM region and ends with an intracellular vestibule with a radius of 0.7 nm. The structure of human homohexameric LRRC8A was found to have a similar extracellular vestibule of 0.74 nm, but the constriction, the transmembrane (TM) region and the intracellular vestibule were wider with radii of 0.38, 2.54, and 1.13 nm, respectively (Kasuya et L-Hydroxyproline al., 2018). It is plausible that the narrowest constriction part of the pore serves as the selectivity filter, which restricts the passage of ions and osmolytes. The radius of constriction was smallest ( 0.1 nm) in the structure reported by Kefauver et al. (2018). It should be noted that the ionic strength conditions and lipid environments significantly affect the packaging of the channel protein generating tighter structures with a narrower pore or.