An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain.
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 alpha-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 alpha-syntrophin (alpha-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 alpha-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 alpha-Syn(-/-) mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but alpha-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus alpha-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 alpha-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule.
Amiry-Moghaddam
Mahmood
M
Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Otsuka
Takashi
T
Hurn
Patricia D
PD
Traystman
Richard J
RJ
Haug
Finn-Mogens
FM
Froehner
Stanley C
SC
Adams
Marvin E
ME
Neely
John D
JD
Agre
Peter
P
Ottersen
Ole Petter
OP
Bhardwaj
Anish
A
D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001834:Body Water; D002135:Calcium-Binding Proteins; D002536:Cerebral Arteries / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016253:Microscopy, Immunoelectron; D009124:Muscle Proteins / Q000378:metabolism*; D015424:Reperfusion
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C091825:syntrophin alpha1