Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema

Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(2):846-51. DOI: 10.1073/pnas.1015217108
Source: PubMed


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.

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    • "et al . , 2011 ) . This result implies that Ca 2+ signals may be evoked by AQP4 - induced astrocyte swelling , rather than by AQP4 directly . Edema induces astrocyte swelling and this is augmented by the presence of AQP4 . Swelling prompts release of toxic neuro - active substances such as glutamate and ATP which mediate aberrant Ca 2+ signaling ( Thrane et al . , 2011 ) . Thus , besides operating as an osmotic flux route , this AQP type may also trigger downstream signaling events and may exacerbate the pathological outcome . Modulation of AQP4 may aid in atten - uating cell swelling and secondary effects such as deleterious ATP release . Activation of purinergic P2X7 receptors by ATP in repair and i"
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