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: 9.81). 01/2011; 108(2):846-51. DOI: 10.1073/pnas.1015217108
Source: PubMed

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.

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Available from: Arnulfo Torres, Aug 19, 2015
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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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    ABSTRACT: Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.
    Frontiers in Cellular Neuroscience 03/2015; 9(34). DOI:10.3389/fncel.2015.00108 · 4.18 Impact Factor
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    • "In the model proposed here, areolar connective tissue fibroblasts use their cytoskeletal machinery to adjust the tension of the matrix, not simply pull on it. The feedback loop allowing this tension regulation appears to involve osmosensation and ATP signaling, reminiscent of mechanisms used by astrocytes to protect the brain from swelling in the presence of hyponatremia [Risher et al., 2009; Thrane et al., 2011]. In the case of myofibroblasts, continuous stretching over several days may give rise to sustained release of ATP and prolonged and activation of P2Y2 receptors causing an increase alpha-smooth muscle actin (alpha-SMA) production and collagen accumulation [Lu et al., 2012]. "
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    ABSTRACT: The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function and cancer. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24521 · 3.37 Impact Factor
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    • "Regardless of different isoforms, during the early stages of brain edema formation astrocyte swell (Nase et al., 2008; Papadopoulos et al., 2004; Risher et al., 2009). A 30% reduction in osmolarity almost instantaneously triggered $20% increase in soma volume, measured in tissue (Thrane et al., 2011), and 5–60% increase in the cross-sectional area of cultured rat astrocytes (Pangršič et al., 2006; Takano et al., 2005). The increase in cell volume may be accompanied by the increased rate of membrane insertion of exocytic vesicles (Pasantes-Morales et al., 2002), although it was suggested that in astrocytes hypotonicity-induced cell swelling is mainly due to the plasma membrane unfolding (Pangršič et al., 2006). "
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    ABSTRACT: Aquaporin 4 (AQP4) is the predominant water channel in the brain, expressed mainly in astrocytes and involved in water transport in physiologic and pathologic conditions. Besides the classical isoforms M1 (a) and M23 (c), additional ones may be present at the plasma membrane, such as the recently described AQP4b, d, e, and f. Water permeability regulation by AQP4 isoforms may involve several processes, such as channel conformational changes, the extent and arrangement of channels at the plasma membrane, and the dynamics of channel trafficking to/from the plasma membrane. To test whether vesicular trafficking affects the abundance of AQP4 channel at the plasma membrane, we studied the subcellular localization of AQP4 in correlation with vesicle mobility of AQP4e, one of the newly discovered AQP4 isoforms. In cultured rat astrocytes, recombinant AQP4e acquired plasma membrane localization, which resembled that of the antibody labeled endogenous AQP4 localization. Under conditions mimicking reactivation of astrocytes (increase in cytosolic cAMP) and brain edema, an increase in the AQP4 plasma membrane localization was observed. The cytoskeleton remained unaffected with the exception of rearranged actin filaments in the model of reactive astrocytes and vimentin meshwork depolymerization in hypoosmotic conditions. AQP4e vesicle mobility correlated with changes in the plasma membrane localization of AQP4 in all stimulated conditions. Hypoosmotic stimulation triggered a transient reduction in AQP4e vesicle mobility mirrored by the transient changes in AQP4 plasma membrane localization. We suggest that regulation of AQP4 surface expression in pathologic conditions is associated with the mobility of AQP4-carrying vesicles.
    Glia 06/2013; 61(6). DOI:10.1002/glia.22485 · 6.03 Impact Factor
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