Syntrophin-Dependent Expression and Localization of Aquaporin-4 Water Channel Protein

The Aquaporin-4 (AQP4) water channel contributes to brain water homeostasis in perivascular astrocyte endfeet where it is concentrated. We postulated that AQP4 is tethered at this site by binding of the AQP4 C terminus to the PSD95-Discs large-ZO1 (PDZ) domain of syntrophin, a component of the dystr...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.14108-14113
Main Authors: Neely, John D., Amiry-Moghaddam, Mahmood, Ottersen, Ole Petter, Froehner, Stanley C., Agre, Peter, Adams, Marvin E.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Aquaporin 4
Aquaporins
Aquaporins - biosynthesis
Aquaporins - genetics
Aquaporins - metabolism
Astrocytes
b-Dystroglycan
Biological Sciences
Brain
Calcium-Binding Proteins
Cell Line
Cell lines
Cell membranes
Cerebellum
CHO Cells
Cricetinae
Cytoskeletal Proteins - metabolism
Dogs
Dystroglycans
Dystrophin - analogs & derivatives
Dystrophin - genetics
Dystrophin - metabolism
Gene Expression
HEK293 cells
Humans
Membrane Glycoproteins - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Muscle Proteins - genetics
Muscle Proteins - metabolism
Proteins
Rats
Rats, Sprague-Dawley
Skeletal muscle
Syntrophin
water channels
Water-Electrolyte Balance
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Summary:The Aquaporin-4 (AQP4) water channel contributes to brain water homeostasis in perivascular astrocyte endfeet where it is concentrated. We postulated that AQP4 is tethered at this site by binding of the AQP4 C terminus to the PSD95-Discs large-ZO1 (PDZ) domain of syntrophin, a component of the dystrophin protein complex. Chemical cross-linking and coimmunoprecipitations from brain demonstrated AQP4 in association with the complex, including dystrophin, β-dystroglycan, and syntrophin. AQP4 expression was studied in brain and skeletal muscle of mice lacking α-syntrophin (α-Syn-/-). The total level of AQP4 expression appears normal in brains of α-Syn-/-mice, but the polarized subcellular localization is reversed. High-resolution immunogold analyses revealed that AQP4 expression is markedly reduced in astrocyte endfeet membranes adjacent to blood vessels in cerebellum and cerebral cortex of α-Syn-/-mice, but is present at higher than normal levels in membranes facing neuropil. In contrast, AQP4 is virtually absent from skeletal muscle in α-Syn-/-mice. Deletion of the PDZ-binding consensus (Ser-Ser-Val) at the AQP4 C terminus similarly reduced expression in transfected cell lines, and pulse-chase labeling demonstrated an increased degradation rate. These results demonstrate that perivascular localization of AQP4 in brain requires α-Syn, and stability of AQP4 in the membrane is increased by the C-terminal PDZ-binding motif.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.241508198