1.A.8.8.5
Aquaporin-4 (AQP4) is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. There are 6 splice variants; the shorter ones assemble into functional, tetrameric square arrays; the longer is palmitoylated on N-terminal cysteyl residues) (Suzuki et al., 2008). The longest, Aqp4e, has a novel N-terminal domain and forms a water channel in the plasma membrane although various shorter variants don't (Moe et al., 2008). AQP4, like AQP0 (1.A.8.8.2), forms water channels but also forms adhesive junctions (Engel et al., 2008) (causes cytotoxic brain swelling in mice (Yang et al., 2008)) Mice lacking Aqp4 have impaired olfactions (Lu et al., 2008). Aqp4 is down regulated in skeletal muscle in muscular dystrophy (Au et al. 2008). The crystal structure is known to 2.8 Å resolution (Tani et al., 2009). The structure reveals 8 water molecules in each of the four channels, supporting a hydrogen-bond isolation mechanism and explains its fast and selective water conduction and proton exclusion (Tani et al., 2009; Cui and Bastien, 2011). It is an important antigen in Neuromyelitis optica (NMO) patients (Kalluri et al., 2011).  A connection has been made between AQP4-mediated fluid accumulation and post traumatic syringomyelia (Hemley et al. 2013).  AQP4 has increased water permeability at low pH, and His95 is the pH-dependent gate (Kaptan et al. 2015).  Also transports NH₃ but not NH₄⁺ (Assentoft et al. 2016). Cerebellar damage following status epilepticus involves down regulation of AQP4 expression (Tang et al. 2017). SUR1-TRPM4 and AQP4 form a complex to increase bulk water influx during astrocyte swelling (Stokum et al. 2017). A mutation, S111T, causes intellectual disability, hearing loss, and progressive gait dysfunction (Berland et al. 2018). As in humans, the chicken ortholog, Aqp4, is found in brain > kidney > stomach (Ramírez-Lorca et al. 2006). A Molecular Dynamics Investigation on Human AQP4 has been published (Marracino et al. 2018). AQP1 and AQP4 activities correlate with the severity of hydrocephalus induced by subarachnoid haemorrhage (Long et al. 2019). Di-lysine motif-like sequences formed by deleting the C-terminal domain of aquaporin-4 prevent its trafficking to the plasma membrane (Chau et al. 2021). Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation (Del Puerto et al. 2021). AQP4 expression is upregulated in cells exposed to dexamethasone, and SUMOylation [Small ubiquitin-like modifiers (SUMOs)] may participate in this regulation (Zhang et al. 2020). Simultaneous calmodulin binding to the N- and C-terminal cytoplasmic domains of aquaporin 4 has been demonstrated (Ishida et al. 2021). Aqp-4 plays a role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after spinal cord injury, SCI. Loss of AQP-4 is associated with reduced spinal edema and improved prognosis after SCI in mice, and downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI (Pan et al. 2022). AQP4 contributes to the migration and proliferation of gliomas, and to their resistance to therapy. In glioma cell cultures, in both subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression (Jia et al. 2022). Aquaporin 4 is required for T cell receptor-mediated lymphocyte activation (Nicosia et al. 2023). Peripheral lung infections influence the blood brain barrier (BBB) water exchange, which appears to be mediated by endothelial dysfunction and is associated with an increase in perivascular AQP4 (Ohene et al. 2023). Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells (Xing et al. 2023). Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke (Stokum et al. 2023). Aquaporin-4 expression and modulation may be important in a rat model of post-traumatic syringomyelia (Berliner et al. 2023).  The Aqp4 water channel may be a drug target for Alzheimer's Disease (Silverglate et al. 2023). A series of 2,4,5-trisubstituted oxazoles 3a-j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). In vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells, and hence it may be considered as a viable drug candidate for the treatment of various lung diseases (Meenakshi et al. 2023).   The effect of AQP4 and its palmitoylation on the permeability of exogenous reactive oxygen species has been considered (Cao et al. 2023). ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema (Thormann et al. 2024).  New biomarkers, such as aquaporin 4 have led to the identification of antigen-specific immune-mediated myelopathies and approved therapies to prevent disease progression (Levy 2024).