An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain

Mahmood Amiry-Moghaddam, Takashi Otsuka, Patricia D. Hurn, Richard J. Traystman, Finn Mogens Haug, Stanley C. Froehner, Marvin E. Adams, John D. Neely, Peter Agre, Ole Petter Ottersen, Anish Bhardwaj

Research output: Contribution to journalArticle

362 Citations (Scopus)

Abstract

The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to α-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding α-syntrophin (α-Syn-/-). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of α-Syn-/- mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in α-Syn-/- mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but α-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus α-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to α-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule.

Original languageEnglish (US)
Pages (from-to)2106-2111
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
StatePublished - Feb 18 2003
Externally publishedYes

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Membranes
Water
Brain Edema
Brain
Transient Ischemic Attack
Dystrophin-Associated Proteins
Aquaporins
Neuropil
Astrocytes
syntrophin
Electron Microscopy
Ischemia
Genes
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. / Amiry-Moghaddam, Mahmood; Otsuka, Takashi; Hurn, Patricia D.; Traystman, Richard J.; Haug, Finn Mogens; Froehner, Stanley C.; Adams, Marvin E.; Neely, John D.; Agre, Peter; Ottersen, Ole Petter; Bhardwaj, Anish.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 4, 18.02.2003, p. 2106-2111.

Research output: Contribution to journalArticle

Amiry-Moghaddam, M, Otsuka, T, Hurn, PD, Traystman, RJ, Haug, FM, Froehner, SC, Adams, ME, Neely, JD, Agre, P, Ottersen, OP & Bhardwaj, A 2003, 'An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 4, pp. 2106-2111. https://doi.org/10.1073/pnas.0437946100
Amiry-Moghaddam, Mahmood ; Otsuka, Takashi ; Hurn, Patricia D. ; Traystman, Richard J. ; Haug, Finn Mogens ; Froehner, Stanley C. ; Adams, Marvin E. ; Neely, John D. ; Agre, Peter ; Ottersen, Ole Petter ; Bhardwaj, Anish. / An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 4. pp. 2106-2111.
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AU - Haug, Finn Mogens

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AU - Adams, Marvin E.

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