Functional down‐regulation of volume‐regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes

Benfenati, Valentina; Nicchia, Grazia Paola; Svelto, María; Rapisarda, C; Frigeri, Antonio; Ferroni, Stefano

doi:10.1111/j.1471-4159.2006.04164.x

Cited by 64 publications

(76 citation statements)

References 77 publications

(206 reference statements)

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“…This efflux provides a driving force for outward water transport (6)(7)(8)20). The upstream mechanisms have remained obscure.…”

Section: Resultsmentioning

confidence: 99%

“…To test the specificity of the assay, the same experiment was performed without the addition of biotin donor. IP experiments were performed on equal amounts of total protein of biotinylated and nonbiotinylated samples (7,8).…”

Section: Methodsmentioning

confidence: 99%

“…Osmolyte efflux through VRAC is thought to provide the driving force for water exit (6,7). The factors that initiate RVD have received comparatively little attention.…”

mentioning

confidence: 99%

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An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

Benfenati

Caprini

Dovizio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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315

335

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Regulatory volume decrease (RVD) is a key mechanism for volume control that serves to prevent detrimental swelling in response to hypo-osmotic stress. The molecular basis of RVD is not understood. Here we show that a complex containing aquaporin-4 (AQP4) and transient receptor potential vanilloid 4 (TRPV4) is essential for RVD in astrocytes. Astrocytes from AQP4-KO mice and astrocytes treated with TRPV4 siRNA fail to respond to hypotonic stress by increased intracellular Ca 2+ and RVD. Coimmunoprecipitation and immunohistochemistry analyses show that AQP4 and TRPV4 interact and colocalize. Functional analysis of an astrocyte-derived cell line expressing TRPV4 but not AQP4 shows that RVD and intracellular Ca 2+ response can be reconstituted by transfection with AQP4 but not with aquaporin-1. Our data indicate that astrocytes contain a TRPV4/AQP4 complex that constitutes a key element in the brain's volume homeostasis by acting as an osmosensor that couples osmotic stress to downstream signaling cascades.water channel | glia | brain edema A basic property of any cell type is the ability to resist volume changes in the face of hypotonic stress. Thus, most cells are equipped with mechanisms that help bring cell volume back toward baseline level in the wake of an osmotically induced swelling response. This volume recovery, termed "regulatory volume decrease" (RVD) (1), plays a critical role in the brain, whose functional and structural integrity depends on finely tuned volume homeostasis at the cellular as well as the organ level.A wealth of data indicates that astroglial cells are essential for the maintenance of volume homeostasis in brain (2). Being equipped with AQP4 water channels in their foot processes at the interface between brain and liquid spaces, astrocytes are the first cells to be exposed to osmotic changes and the first cells to swell in response to hypo-osmotic stress (3-5). Further, the proximity of the astroglial processes to the subarachnoidal space and vessels (which act as sinks for excess osmolytes) places astroglia in a unique position for mediating regulatory volume changes, on the part of the astrocytic syncytium and the brain as a whole.A full mechanistic understanding of RVD would pave the way for more sophisticated measures to curtail pathological changes in brain water transport and distribution, as seen in brain tumors, stroke, and several other acute conditions that carry a high morbidity and lethality because of the loss of volume homeostasis. Future drugs affecting AQP4-mediated water transport would be expected to alleviate the acute consequences of inadvertent changes in osmotic driving forces. However, because the lipid bilayer of plasma membranes allows water diffusion (albeit to a restricted extent compared with membranes containing aquaporins), the long-term consequences of osmotic challenges can be offset only by manipulating the osmotic gradients per se. In this context, the RVD mechanisms stand out as targets of potential pharmacological interest (1, 6).Previous studies of t...

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“…This efflux provides a driving force for outward water transport (6)(7)(8)20). The upstream mechanisms have remained obscure.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

Benfenati

Caprini

Dovizio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

315

335

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“…Upregulation of AQP5 on osmotic changes has been shown in submandibular acinar cells [31]. There could also be functional interaction between AQPs and ion channels for volume regulation, as shown for swellingactivated Cl − conductance in AQP4 knockdown astrocytes [32].…”

Section: The Study Of Water Channels In Sperm Volume Regulationmentioning

confidence: 96%

Aquaporins in spermatozoa and testicular germ cells: identification and potential role

Yeung¹

2010

Asian J Androl

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Mammalian spermatozoa have relatively high water permeability and swell readily, as in the hypo-osmotic swelling test used in the andrology clinic. Physiologically, spermatozoa experience changes in the osmolality of the surrounding fluids in both the male and the female tracts on their journey from the testis to the ovum. Sperm volume regulation in response to such osmotic challenges is important to maintain a stable cell size for the normal shape and function of the sperm tail. Alongside ion channels for the fluxes of osmolytes, water channels would be crucial for sperm volume regulation. In contrast to the deep knowledge and numerous studies on somatic cell aquaporins (AQPs), the understanding of sperm AQPs is limited. Among the 13 AQPs, convincing evidence for their presence in spermatozoa has been confined to AQP7, AQP8 and AQP11. Overall, current findings indicate a major role of AQP8 in water influx and efflux for sperm volume regulation, which is required for natural fertilization. The preliminary data suggestive of a role for AQP7 in sperm glycerol metabolism needs further substantiation. The association of AQP11 with the residual cytoplasm of elongated spermatids and the distal tail of spermatozoa supports the hypothesis of more than just a role in conferring water permeability and also in the turnover and recycling of surplus cellular components made redundant during spermiogenesis and spermiation. This would be crucial for the maintenance of a germinal epithelium functioning efficiently in the production of spermatozoa.

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“…49 Thus, inhibition of AQP4 channel function could reduce edema during stroke, and this is a target for drug development. In addition, reduced abundance of AQP4 diminishes the function of volume-regulated anion channels (VRAC) in astrocyte cultures, 50 which could account for some of its protective effects. Notably, because AQP4 also enhances astrocyte migration and glial scar formation, AQP4 inhibitors may also be useful to reduce glial scar formation.…”

Section: Astrocytes Edema and Volume Regulation In Strokementioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Functional down‐regulation of volume‐regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes

Cited by 64 publications

References 77 publications

An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes

Aquaporins in spermatozoa and testicular germ cells: identification and potential role

Targeting Astrocytes for Stroke Therapy

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