Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein

John D. Neely, Mahmood Amiry-Moghaddam, Ole Petter Ottersen, Stanley C. Froehner, Peter Agre, Marvin E. Adams

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347 Scopus citations


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-1-). The total level of AQP4 expression appears normal in brains of α-Syn-1- 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-1- 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-1- 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.

Original languageEnglish (US)
Pages (from-to)14108-14113
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Nov 20 2001

ASJC Scopus subject areas

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