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).