AQP4 (aquaporin 4)

2012-12-01   Domenico Ribatti , Beatrice Nico 

Department of Basic Medical Sciences, Neurosciences, Sensory Organs, University of Bari Medical School, Bari, Italy

Identity

HGNC
LOCATION
18q11.2
LOCUSID
ALIAS
MIWC,WCH4
FUSION GENES

DNA/RNA

Atlas Image

Description

Sequence length: 323 AA.
Total number of exons: 5.

Proteins

Expression

In the brain, AQP-4 is expressed at the glia limitans everywhere, ependymal lining, cerebellum, hippocampal dentate gyrus, and in the supraoptic and paraventricular nuclei of the hypothalamus. Low AQP-4 expression has also been found in the neocortex, hippocampal areas, nucleus of the stria terminalis, and the medial habenular nucleus (Venero et al., 1999). AQP-4 is expressed in a polarized way by astrocytic foot processes at the borders between major water compartments and the brain parenchyma (Nielsen et al., 1997; Rash et al., 1998). The perivascular expression of AQP4 coincides with the K+ channel protein Kir 4.1 at blood-brain barrier (BBB) level (Nagelhus et al., 1999).

Localisation

Subcellular localization: membrane; multi-pass membrane protein.

Function

AQP4 is implicated in the pathogenesis of normal pressure hydrocephalus, pseudotumor cerebri and cerebral edema (Badaut et al., 2002). AQP4-null mice have a much better outcome after water intoxication, meningitis and brain ischemia (Manley et al., 2004). AQP4-null mice have a significantly greater increase in brain water content and intracranial pressure than the wild-type mice, suggesting that brain water elimination is defective after AQP4 deletion (Papadopoulos et al., 2004a; Papadopoulos and Verkman, 2007). AQP4, by controlling the bidirectional water flux is responsible for the formation of cellular brain edema, but counteracts vasogenic edema (Saadoun et al., 2002). In vasogenic edema, AQP4 is thought to have a protective role, through brain water clearance, whereas in cytotoxic edema it is the main contributor to astrocytic cell swelling (Manley et al., 2004; Papadopoulos et al., 2004a; Papadopoulos et al., 2004 b). Water intoxicated AQP4-null mice show a significant reduction in astrocytic foot process swelling and a decrease in brain water content (Manley et al., 2000).
Nicchia et al. (2005) have shown that AQP-4 knockdown in rat and human cells was associated with a depolymerization of actin with a change of morphology characterized by a remarkable F-actin cytoskeleton rearrangement in AQP-4 knock-down mouse astrocytes. Moreover, AQP-4 can interact with α-syntrophin, a member rof the dystrophin-dystroglycan complex, indicating an involvement of AQP-4 protein in altering the cell cytoskeleton (Warth et al., 2004). Accordingly, Nico et al. have demonstrated that in the brain of mdx mouse, an animal model of the Duchenne muscular dystrophy, glial cells showed a significant reduction in both protein and mRNA content of the dystrophin-associated proteins (DAPs), including AQP-4, Kir 4.1, syntrophin and α-β-dystroglycan, coupled with a decrease in dystrophin isoform (Dp71) (Nico et al., 2010). Moreover, alterations of the vascular basement membrane and reduction of the expression of its components laminin and agrin and translocation of α-β-dystroglycan receptors in the glial cytoplasmic endfeet have been demonstrated (Nico et al., 2010).

Homology

The AQP4 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, M. oryzae, A. thaliana, and rice.

Description

Subunit structure: homotetramer. Part of a complex containing MLC1, TRPV4, HEPACAM and ATP1B1.
Domain: contains two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motiv Asn-Pro-Ala (NPA).
Post-translational modification: phosphorylation by PKC at Ser-180 reduces conductance by 50%. Phosphorylation by PKG at Ser-111 in response to glutamates increases conductance by 40%.
Structure: AQP4, a small 30-kDa monomer, is a hydrophobic transmembrane protein with cytosolic amino and carboxy terminal ends (Verkman, 2005). The molecule spans the cell membrane 6 times, forming 5 interhelical loops designated as A, C, and E on the extracellular surface and B and D on the intracellular surface. A consistent 3-amino acid hydrophobic motif, asparginine-proline-alanine (NPA), is present in both the B and E loops. Each monomer folds into a structure that forms an independent water channel, characterized by wide external openings and a narrow central constriction where the NPA motifs interact. AQP4 monomers assemble into tetramers, with each monomer being individually functional. Water movement through the channel is governed by an osmotic gradient across the membrane, with flow limited by size restriction and electrostatic repulsion.
Variants: AQP4 occurs in mainly two splices variants, the M1 and M23 isoform (Jung et al., 1994). M23 forms higher order assemblies within the plasma membrane, termed orthogonal arrays of particles (OAPs), whereas M1 exists as individuals tetramers. Phosphorylation of AQP4 can also regulate array formation.

Implicated in

Entity name
Melanoma
Note
Melanoma cells implanted into the striatum of wild type and AQP4-null mice produce peritumoral edema and comparable sized-tumors in both groups after a week. However, the AQP4-null mice have a higher intracerebral pressure and water content (Manley et al., 2004).
Entity name
Astrocytoma
Note
AQP4 expression has also been demonstrated to be up-regulated in edematous astrocytomas and metastatic tumors (Saadoun et al., 2002). An increased AQP4 expression has been demonstrated in glioblastoma multiforme (GBM) together with loss of polarized expression around the vessels and an AQP4 redistribution in glioma cells (Warth et al., 2004; Warth et al., 2005; Warth et al., 2007). Warth et al. (2007) investigated grade I-IV glioma by immunohistochemistry and the prognostic significance for patients survival. In gliomas, a remarkable de novo AQP4 redistribution was observed in comparison with normal central nervous system tissue. Moreover, the highest membranous staining levels were seen in pilocytic astrocytomas WHO grade I and grade IV glioblastomas, both significantly higher than in WHO grade II. AQP4 up-regulation was associated with brain edema formation and no association between survival and WHO grade-dependent AQP4 expression was seen. Moreover, in glioma cells co-localization of AQP4 with K+ channel protein Kir 4.1 is abolished and a mislocation of both Kir channels and AQP4 has been reported (Warth et al., 2007), suggesting that this molecular rearrangement occurs as a reaction to BBB damages, facilitating edema fluid flow. Mou et al. (2010) investigated changes of AQP4 protein expression in normal brain and in brain glioma tumor and peritumoral edematous tissues and analyzed the relationship of AQP-4 protein with edema index, VEGF and hypoxia inducible factor 1 alpha (HIF-1α) protein. They demonstrated that expression of AQP-4 was higher in the tumor and highest in the peritumor tissue. Moreover, AQP-4 protein in tumor tissue of gliomas of different grades was not statistically different. In normal brain tissues, AQP-4 was mainly expressed in the foot processes of astrocytes, but rare in the parenchyma. Finally, the degree of peritumoral edema positively correlated with the expression level of AQP-4 protein and this latter correlated with VEGF and HIF-1α expression. Nico et al. (2009) evaluated AQP4 expression and content in GBM and correlated with VEGF-VEGFR-2 expression. They demonstrated that in the relapse after chemotherapy and radiotherapy, AQP4 reduced in parallel with VEGF-VEGFR-2 expression as compared with primary tumors, and in the peripheral areas of relapsed tumors AQP4 mimicked normal findings of perivascular rearrangements. These data indicate that in GBM chemotherapy and radiotherapy induce a down-regulation in AQP4 expression restoring its perivascular rearrangement and suggest its potential role in the resolution of brain edema. Moreover, the normally polarized rearrangement of AQP4 in peripheral areas in tumor specimens obtained after combined chemotherapy and radiotherapy could be expression of a process of normalization of tumor blood vessels. Tumor implantation experiments into AQP4-null mice have demonstrated that these mice have an increased intracranial pressure than wild-type controls (Papadopoulos et al., 2004a; Papadopoulos et al., 2004b). McCoy et al. (2010) using D54MG glioma cells stably transfected with either AQP1 or AQP4 demonstrated that protein kinase C (PKC) activity regulates water permeability through phosphorylation of AQP4. Activation of PKC with either phorbol 12-myristate 13-acetate or thrombin enhanced AQP4 phosphorylation, reduced water permeability and significantly decreased tumor cell invasion. Conversely, inhibition of PKC activity with chlerythrine reduced AQP4 phosphorylation, enhanced water permeability and tumor cell invasion.
Entity name
Meningioma
Note
Ng et al. (2009) demonstrated that overexpression of AQP4 in meningiomas was associated with significant peritumoral edema.
Entity name
Therapeutic perspectives
Note
Inhibition of AQPs expression and/or AQP-mediated water influx by acetozolamide, cyclophosphamide, topiramate, thiopenthal, phenobarbital and propofol, affects cancer cell proliferation, migration, metastasis and angiogenic potential (Monzani et al., 2007).
Inhibition of AQP-4 expression (by small interference RNA technology) or their function (with a blocking antibody or a small inhibitory molecule) may result in increased intracellular acidosis and cytotoxicity and reduced invasive potential of glioma cells. Ding et al. (2011), using small interference RNA and a pharmaceutical inhibitor to knock down the expression of AQP-4, demonstrated a specific and massive impairment of glioblastoma cell migration and invasion in vitro and in vivo. Moreover, they showed that down-regulation of matrix metalloproteinase-2 (MMP-2) expression coincides with decreased cell invasive ability. Accordingly, Badaut et al. (2011) using RNA interference have demonstrated that brain water motility decreases after astrocyte AQP-4 inhibition.
Corticosteroids are largely used in combination with chemotherapy and contribute to significantly reduce peritumoral brain edema by decreasing the permeability of tumor vessels and/or enhance the clearance of extracellular water (Sinha et al., 2004). Animal experiments showed a decrease of cerebral AQP-4 protein expression upon dexamethasone treatment (Ron et al., 2005), suggesting that AQP-4 may be considered one of the major molecular targets of the well-functioning steroid treatment in brain edema formation. Moreover, corticosteroids reduced AQP-4 mRNA level in experimental brain tumor model and after intracerebral hemorrhage in rats (Heiss et al., 1996; Gu et al., 2007). The evidence that AQP-4 facilitates the migration of reactive astrocytes towards an injury site and the infiltration of malignant astrocytes in glioblastoma (Verkman et al., 2008) suggests that AQP-4 inhibitors may reduce reactive gliosis and infiltration of astrocytes.

Bibliography

Pubmed IDLast YearTitleAuthors
208773852011Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference.Badaut J et al
119195082002Aquaporins in brain: distribution, physiology, and pathophysiology.Badaut J et al
214241252011Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells.Ding T et al
172400622007Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats.Gu YT et al
88233051996Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.Heiss JD et al
75289311994Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance.Jung JS et al
155614132004New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice.Manley GT et al
106551032000Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.Manley GT et al
197618162010Water permeability through aquaporin-4 is regulated by protein kinase C and becomes rate-limiting for glioma invasion.McCoy ES et al
179796732007The water channels, new druggable targets to combat cancer cell survival, invasiveness and metastasis.Monzani E et al
204677852010AQP-4 in peritumoral edematous tissue is correlated with the degree of glioma and with expression of VEGF and HIF-alpha.Mou K et al
100886711999Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains.Nagelhus EA et al
191530452009Aquaporin-4 expression is increased in edematous meningiomas.Ng WH et al
161031092005New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43.Nicchia GP et al
198362272009Aquaporin-4 contributes to the resolution of peritumoural brain oedema in human glioblastoma multiforme after combined chemotherapy and radiotherapy.Nico B et al
207143242010Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse.Nico B et al
89877461997Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain.Nielsen S et al
173478372007Aquaporin-4 and brain edema.Papadopoulos MC et al
97517761998Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord.Rash JE et al
159072792005Ontogeny and the effects of corticosteroid pretreatment on aquaporin water channels in the ovine cerebral cortex.Ron NP et al
117967802002Aquaporin-4 expression is increased in oedematous human brain tumours.Saadoun S et al
154894042004Effects of dexamethasone on peritumoural oedematous brain: a DT-MRI study.Sinha S et al
106135141999Detailed localization of aquaporin-4 messenger RNA in the CNS: preferential expression in periventricular organs.Venero JL et al
183114712008Aquaporins--new players in cancer biology.Verkman AS et al
160792752005More than just water channels: unexpected cellular roles of aquaporins.Verkman AS et al
147353052004Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae.Warth A et al
157232362005Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors.Warth A et al
173350822007Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood-brain barrier disturbance but not with patient survival.Warth A et al

Other Information

Locus ID:

NCBI: 361
MIM: 600308
HGNC: 637
Ensembl: ENSG00000171885

Variants:

dbSNP: 361
ClinVar: 361
TCGA: ENSG00000171885
COSMIC: AQP4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000171885ENST00000383168P55087
ENSG00000171885ENST00000383168F1DSG4
ENSG00000171885ENST00000383170H0Y3H5
ENSG00000171885ENST00000440832P55087
ENSG00000171885ENST00000578776J3KRM4
ENSG00000171885ENST00000581374P55087
ENSG00000171885ENST00000672188F1DSG4

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
Vasopressin-regulated water reabsorptionKEGGko04962
Vasopressin-regulated water reabsorptionKEGGhsa04962
Bile secretionKEGGko04976
Bile secretionKEGGhsa04976
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Aquaporin-mediated transportREACTOMER-HSA-445717
Passive transport by AquaporinsREACTOMER-HSA-432047
Vasopressin regulates renal water homeostasis via AquaporinsREACTOMER-HSA-432040

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
199381042009Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica.196
244155682014Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.154
168319652006Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression.139
193837902009Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance.119
226086672012Aquaporin 4 and neuromyelitis optica.107
212628392011An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes.84
214545922011Binding affinity and specificity of neuromyelitis optica autoantibodies to aquaporin-4 M1/M23 isoforms and orthogonal arrays.83
213211932011Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica.74
278938742017Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains.60
223930492012Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays.55

Citation

Domenico Ribatti ; Beatrice Nico

AQP4 (aquaporin 4)

Atlas Genet Cytogenet Oncol Haematol. 2012-12-01

Online version: http://atlasgeneticsoncology.org/gene/684/aqp4