Aquaporin-4

The aquaporins (AQPs) are a family of membrane proteins that function as “water channels” in many cell types and tissues in which fluid transport is crucial.  The AQPs are small hydrophobic proteins (~30 kDa monomer) that facilitate bi-directional water transport in response to osmotic gradients.  Aquaporin-4 (AQP4) is expressed by CNS glial cells, especially at specialized membrane domains including astroglial endfeet in contact with blood vessels and astrocyte membranes that ensheathe glutamatergic synapses.  Activity-induced radial water fluxes in neocortex have been demonstrated that may represent water movement via aquaporin channels in response to physiological activity.

Figure 1. Aquaporin-4 forms a membrane pore that is water-selective. Water can flow bidirectionally down its osmotic gradient.

Knockout mice have suggested a functional role for AQP4 in brain water transport. Mice deficient in AQP4 (AQP4-/-) have markedly decreased accumulation of brain water (cerebral edema) following water intoxication and focal cerebral ischemia and impaired clearance of brain water in models of vasogenic edema. Similarly, mice deficient in dystrophin or α-syntrophin, in which there is mislocalization of the AQP4 protein, also demonstrate attenuated cerebral edema.

Figure 2. Sagittal fluorescent immunohistochemical montage demonstrating widespread expression of AQP4 in the mouse brain.

In addition to modulation of brain water transport, AQP4 and its known molecular partners have been hypothesized to modulate ion homeostasis. During rapid neuronal firing, extracellular [K+] increases from ~3 mM to a maximum of 10-12 mM; and K+ released by active neurons is thought to be primarily taken up by glial cells. Such K+ reuptake into glial cells could be AQP4-dependent, as water influx coupled to K+ influx is thought to underlie activity-induced glial cell swelling.

In collaboration with several other research groups, our laboratory has been interested for several years in elucidating the roles of AQP4 in the CNS (brain and spinal cord). We have found that AQP4-/- mice have marked alterations in seizure susceptibility, K+ regulation and response to spinal cord injury. Further work is underway in the laboratory using the AQP4-/- mice as a critical research tool to address fundamental questions about the functional significance of water transport and ion homeostasis in health and disease.

Figure 3. High-magnification examples of hippocampal AQP4 immunoreactivity colocalizing with S100β, a marker of astrocytes.