title: Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema.
abstract: Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca(2+) signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo two-photon imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca(2+) spikes and that deletion of Aqp4 reduces these signals. The Ca(2+) signals are partly dependent on activation of P2 purinergic receptors, which was judged from the effects of appropriate antagonists applied to cortical slices. Supporting the involvement of purinergic signaling, osmotic stress was found to induce ATP release from cultured astrocytes in an AQP4-dependent manner. Our results suggest that AQP4 not only serves as an influx route for water but also is critical for initiating downstream signaling events that may affect and potentially exacerbate the pathological outcome in clinical conditions associated with brain edema.
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Thrane
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Rappold
authors.forename: Takumi
authors.initials: T
authors.lastname: Fujita
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Torres
authors.forename: Lane K
authors.initials: LK
authors.lastname: Bekar
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.forename: Weiguo
authors.initials: W
authors.lastname: Peng
authors.forename: Fushun
authors.initials: F
authors.lastname: Wang
authors.forename: Vinita
authors.initials: V
authors.lastname: Rangroo Thrane
authors.forename: Rune
authors.initials: R
authors.lastname: Enger
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Haj-Yasein
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Skare
authors.forename: Torgeir
authors.initials: T
authors.lastname: Holen
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
authors.forename: Erlend A
authors.initials: EA
authors.lastname: Nagelhus
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D051401:Aquaporin 4 / Q000737:chemistry* / Q000235:genetics*; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D004487:Edema / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009995:Osmosis; D017785:Photons; D015398:Signal Transduction; D014867:Water / Q000737:chemistry
chemical_list: D051401:Aquaporin 4; D014867:Water; D000255:Adenosine Triphosphate; D002118:Calcium