Figure 1.

AQP4 localization in the CNS. (A) AQP4 (blue) is located within astrocyte endfeet processes surrounding blood vessels in both brain tissue and the BBB. The inset shows the crystal structure of human AQP4 (PDB code 3GD8). AQP4 assembles as a tetramer with each monomer comprising six transmembrane helices and two half-helices (grey). The two half helices harbour the aquaporin signature motif (NPA) as well as part of the aromatic-arginine (ar/R) motif that functions as a selectivity filter. Within the pore, water molecules (red spheres) align in a single file. (B) AQP4 is localized at the astrocyte component of the tripartite synapse. During neurotransmission, neurons release mediators and neurotransmitters from synaptic nerve terminals (affecter cells) into the synaptic cleft to communicate with other neurons (effector cells). This synaptic activity induces an increase in intracellular Ca²⁺ concentration, which is accompanied by changed water and solute concentrations in astrocytes, leading to the release of glutamate and other gliotransmitters. This gliotransmission results in negative feedback to the presynaptic neurons to modulate neurotransmission. AQP4 plays an essential role in maintaining water homeostasis during this process. (C) In ventricles, AQPs are present within ependymal cells lining the brain-CSF interfaces (left inset). AQP4 is localized to the basolateral membrane of ependymal cells and the endfeet of contacting astrocytes (right inset). AQP1 (purple) is localized to the apical membrane of the choroid plexus epithelium.^6,30 (D) CSF within the subarachnoid and cisternal spaces flows into the brain specifically via periarterial spaces and then exchanges with brain interstitial fluid facilitated by AQP4 water channels that are positioned within perivascular astrocyte endfoot processes.