Aquaporin water channels in the nervous system

Abstract

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage.

Figure 1. Sequence and structural features of AQP4

a | The schematic depicts the primary amino acid sequence and membrane topology of aquaporin 4 (AQP4). This AQP has eight membrane-embedded helical segments, which are labelled M1–M8, and two translation initiation sites — Met1 and Met23 (black) — corresponding to the two AQP4 isoforms, M1 and M23, respectively. AQP4 tetramers can form orthogonal arrays of particles (OAPs) through intermolecular N-terminal associations between M23 isoforms involving the residues highlighted in purple. The residues in green prevent N-terminal associations between M1 AQP4 molecules. Cysteine residues (in blue) are sites of palmitoylation, and are involved in regulating OAP assembly. The C terminus of AQP4 contains a PDZ domain (in green) that may be involved in protein–protein interactions. b | X-ray crystal structure of human AQP4 (RCSB Protein Data Bank ID: 3GD8) shows the eight membrane-embedded helical segments. c | Freeze-fracture electron micrograph (FFEM) of M23-AQP4-expressing Chinese hamster ovary cells shows that AQP4 OAPs are supermolecular assemblies that have a cobblestone-like array structure (left panel). The middle panel shows a super-resolution micrograph, which was obtained by direct stochastic optical reconstruction microscopy (dSTORM), of cells co-expressing a green fluorescent variant of M23-AQP4 and a red fluorescent variant of M1-AQP4 (REF. 18). From such micrographs, it has been determined that OAPs have a M23-AQP4-enriched core, with M1-AQP4 being found in the periphery of these structures (diagrammatically depicted in the inset on the right). The left panel of part c is reproduced, with permission, from REF. © (1996) American Society for Biochemistry and Molecular Biology. The middle and right panels in part c are modified, with permission, from REF. © (2012) The Company of Biologists Ltd.

Figure 2. Aquaporin expression in the nervous system

a | In the retina, aquaporin 4 (AQP4) is expressed in its vitreous-facing ciliary epithelium and in perivascular processes of Müller cells. b | In the olfactory epithelium, AQP4 is expressed in olfactory epithelium support cells. c | In the inner ear, AQP4 can be detected in the inner sulcus, and in Claudius and Hensen cells in the cochlea, and AQP1 can be found in intermediate cells and fibrocytes of the spiral ligament. d | In the brain, AQP4 is primarily expressed in astrocyte processes of the glia limitans externa and perivascular astrocyte foot processes. AQP4 is also expressed in the basolateral cell plasma membrane of ependymal cells and in subependymal astrocyte processes of the glia limitans externa. AQP1 is expressed in the cerebrospinal fluid (CSF)-facing plasma membrane of the choroid plexus epithelium. The sites of AQP9 expression remain unclear. e | In the spinal cord, AQP1 is expressed in non-myelinated dorsal root ganglion (DRG) neurons, whereas AQP4 is expressed in astrocyte processes of the glia limitans externa and in perivascular astrocyte foot processes. f | In the enteric nervous system, AQP1 is expressed in glia, whereas AQP4 is found in neurons and glia of the submucosal and myenteric plexuses. g | In the spine, AQP9 is expressed in osteoclasts within the vertebrae, and AQP1 and AQP3 are found in nucleus pulposus cells.

Figure 3. Routes of water flow into and out of the CNS in brain oedema

In cytotoxic oedema, water enters the CNS through aquaporin 4 (AQP4) that is located in perivascular astrocyte foot processes. In vasogenic oedema, CNS water entry is AQP4-independent and occurs through intercellular spaces. In hydrocephalic oedema, water enters the brain through AQP4 in ependymal cells and subependymal astrocytes. Oedema fluid is eliminated through three AQP4-dependent routes: from astrocyte foot processes into the bloodstream, across subpial astrocyte processes and pial cells into subarachnoid cerebrospinal fluid (CSF), and across subependymal astrocyte processes and ependyma into ventricle.

Figure 4. Aquaporin 4 involvement in astrocyte migration and neuroexcitation

a | Aquaporin 4 (AQP4) has a proposed role in astrocyte migration. Water is driven into the cytoplasm primarily through AQP4 in the lamellipodium by an osmotic gradient created by actin depolymerization and active solute influx (left), facilitating lamellipodial extension in the direction of cell migration (right). b | AQP4 is also proposed to have a role in neuroexcitation outside the synaptic cleft (left panel). Neuroexcitation involves isosmolar K⁺ release by neurons and uptake of K⁺ and water by astrocytes (centre panel). AQP4 facilitates water entry into astrocytes, resulting in contraction of the extracellular space (ECS) volume and increased ECS K⁺ concentration ([K⁺]; right panel), which further drives astrocyte K⁺ uptake.

Figure 5. Proposed role of aquaporin 4 in the pathogenesis of neuromyelitis optica

a | Circulating aquaporin 4 (AQP4)-specific immunoglobulin G (IgG) enters the CNS and binds to AQP4 on astrocyte foot processes. Complement is activated via the classical pathway with deposition of C5b–C9 complexes in astrocyte cell plasma membranes. b | Activated complement components attract peripheral leukocytes (primarily neutrophils and eosinophils) into the lesion, which degranulate, causing astrocyte death. c | Chemokines (from dying astrocytes and activated leukocytes) attract macrophages, causing death of oligodendrocytes and neurons. d | Microglia enter the lesion as well as reactive astrocytes, which express AQP4 and form a glial scar. The lesion core is necrotic with a macrophage infiltrate.