The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

Brain function is inextricably coupled to water homeostasis. The fact that most of the volume between neurons is occupied by glial cells, leaving only a narrow extracellular space, represents an important challenge, as even small extracellular volume changes will affect ion concentrations and therefore neuronal excitability. Further, the ionic transmembrane shifts that are required to maintain ion homeostasis during neuronal activity must be accompanied by water. It follows that the mechanisms for water transport across plasma membranes must have a central part in brain physiology. These mechanisms are also likely to be of pathophysiological importance in brain oedema, which represents a net accumulation of water in brain tissue. Recent studies have shed light on the molecular basis for brain water transport and have identified a class of specialized water channels in the brain that might be crucial to the physiological and pathophysiological handling of water.

The molecular basis of water transport in the brain.

Systemic osmoregulation is a vital process whereby changes in plasma osmolality, detected by osmoreceptors, modulate ingestive behaviour, sympathetic outflow and renal function to stabilize the tonicity and volume of the extracellular fluid. Furthermore, changes in the central processing of osmosensory signals are likely to affect the hydro-mineral balance and other related aspects of homeostasis, including thermoregulation and cardiovascular balance. Surprisingly little is known about how the brain orchestrates these responses. Here, recent advances in our understanding of the molecular, cellular and network mechanisms that mediate the central control of osmotic homeostasis in mammals are reviewed.

http://www.med.uottawa.ca/courses/nsc5104/assets/documents/dr_renaud2009/nrn2400.pdf

Central mechanisms of osmosensation and systemic osmoregulation.

The neurobiology of glia in the context of water and ion homeostasis

The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited.

To characterize the volume-sensitive, osmolyte permeable anion channels responsible for the osmodependent release of taurine from supraoptic nucleus (SON) astrocytes, we investigated the pharmacological properties of the [(3)H]-taurine efflux from acutely isolated SON. Taurine release induced by hypotonic stimulus (250 mosmol l(-1)) was not antagonized by the taurine transporter blocker guanidinoethyl sulphonate, confirming the lack of implication of the transporter. The osmodependent release of taurine was blocked by a variety of Cl(-) channel inhibitors with the order of potency: NPPB>niflumic acid>DPC>DIDS>ATP. On the other hand, release of taurine was only weakly affected by other compounds (dideoxyforskolin, 4-bromophenacyl bromide, mibefradil) known to block volume-activated anion channels in other cell preparations, and was completely insensitive to tamoxifen, a broad inhibitor of these channels. Although the molecular identity of volume-sensitive anion channels is not firmly established, a few genes have been postulated as potential candidates to encode such channels. We checked the expression in the SON of three of them, ClC(3), phospholemman and VDAC(1), and found that the transcripts of these genes are found in SON neurons, but not in astrocytes. Similar observation was previously reported for ClC(2). In conclusion, the osmodependent taurine permeable channels of SON astrocytes display a particular pharmacological profile, suggesting the expression of a particular type or subtype of volume-sensitive anion channel, which is likely to be formed by yet unidentified proteins.

/pdf/pharmacological-characterization-of-volume-sensitive-taurine-bhvuov249f.pdf

Pharmacological characterization of volume-sensitive, taurine permeable anion channels in rat supraoptic glial cells

In the supraoptic nucleus, taurine, selectively released in an osmodependent manner by glial cells through volume-sensitive anion channels, is likely to inhibit neuronal activity as part of the osmoregulation of vasopressin release. We investigated the involvement of various kinases in the activation of taurine efflux by measuring [3H]taurine release from rat acutely isolated supraoptic nuclei.


The protein tyrosine kinase inhibitors genistein and tyrphostin B44 specifically reduced, but did not suppress, both the basal release of taurine and that evoked by a hypotonic stimulus. Inhibition of tyrosine phosphatase by orthovanadate had the opposite effect.


The tyrosine kinase and phosphatase inhibitors shifted the relationship between taurine release and medium osmolarity in opposite directions, suggesting that tyrosine phosphorylation modulates the osmosensitivity of taurine release, but is not necessary for its activation.


Genistein also increased the amplitude of the decay of the release observed during prolonged hypotonic stimulation. Potentiation of taurine release by tyrosine kinases could serve to maintain a high level of taurine release in spite of cell volume regulation.


Taurine release was unaffected by inhibitors and/or activators of PKA, PKC, MEK and Rho kinase.


Our results demonstrate a unique regulation by protein tyrosine kinase of the osmosensitivity of taurine efflux in supraoptic astrocytes. This points to the presence of specific volume-dependent anion channels in these cells, or to a specific activation mechanism or regulatory properties. This may relate to the particular role of the osmodependent release of taurine in this structure in the osmoregulation of neuronal activity.







Taurine is an abundant sulfonic β-amino acid present intracellularly at high concentration and best known for its active participation in cell volume regulation (Huxtable, 1992; Pasantes-Morales & Schousboe, 1997). Cells exposed to hypotonic medium swell by water incorporation and progressively recover their initial volume despite the lower tonicity of the extracellular medium through a process known as regulatory volume decrease (RVD; Hoffman & Dunham, 1995; Lang et al. 1998). RVD is achieved via the efflux of inorganic ions and organic osmolytes that include taurine. A large body of evidence supports the notion that taurine leaves the cell upon swelling through ubiquitous, broadly permeable volume-sensitive anion channels, referred to as volume-sensitive organic osmolyte and anion channels (VSOACs), volume-regulated anion channels, or outwardly rectifying Cl− channels (Strange et al. 1996; Okada, 1997; Nilius et al. 1997; Kirk, 1997). This conclusion is based on the one hand on the strong similarities between volume-dependent taurine efflux and swelling-induced Cl− currents through VSOACs with regard to their pharmacological properties, their kinetics of activation, and their implication in volume regulation, and on the other hand on the direct taurine permeability of VSOACs (Strange et al. 1996; Basavappa & Ellory, 1996; Pasantes-Morales & Schousboe, 1997; Kirk, 1997; Nilius et al. 1997; Manolopoulos et al. 1997). However, as mentioned by Kirk (1997), the correspondence between swelling-induced taurine efflux and VSOACs is only correlative, and has yet to be proven, and evidence for alternative taurine pathways has been provided in some cell preparations.

VSOACs have been studied in a wide variety of cell preparations, and if these studies agree on several common features of the channels, they also point to different properties depending on the cell model used, notably regarding their activation and regulation. VSOACs are characterised by an outward rectification, an inactivation at positive potentials, a 20–90 pS conductance, a weak selectivity among anions and a high permeability to the organic osmolytes myo-inositol and taurine (Strange et al. 1996; Nilius et al. 1997; Kirk, 1997). The mechanism of activation of VSOACs/taurine efflux upon cell swelling is still poorly understood. It has been argued that membrane stretch is unlikely to directly activate VSOACs (Strange et al. 1996; Okada, 1997; Nilius et al. 1997). Reduction of intracellular ionic strength has been proposed as the initial trigger of channel activation (Voets et al. 1999), although other authors have found that ionic strength regulates the volume sensitivity of the channels (Cannon et al. 1998). In most preparations, activation of VSOACs is independent of changes in intracellular Ca2+ (Strange et al. 1996; Pasantes-Morales & Schousboe, 1997; Okada, 1997). Implication of phosphorylation events is also controversial. Indeed, if VSOAC activation generally requires the presence of intracellular ATP (Strange et al. 1996; Basavappa & Ellory, 1996; Nilius et al. 1997; Crepel et al. 1998; Miley et al. 1999), its hydrolysis is not necessary in many cell preparations as ATP can be replaced by non-hydrolysable analogues (Strange et al. 1996; Okada, 1997; Nilius et al. 1997; Miley et al. 1999; Bond et al. 1999). This observation argues for a lack of involvement of protein kinases in the activation mechanism. On the other hand, ATP hydrolysis appears critical in other cell preparations (Meyer & Korbmacher, 1996; Crepel et al. 1998), and protein tyrosine kinases (PTKs) have been proposed to play a pivotal role in the activation of VSOACs in many cell types including cultured astrocytes (Crepel et al. 1998; Mongin et al. 1999), cardiac myocytes (Sorota, 1995), lymphocytes (Lepple-Wienhues et al. 1998), endothelial (Voets et al. 1998) and epithelial cells (Tilly et al. 1993). In cultured astrocytes, this process requires further activation of the mitogen-activated protein kinases (MAPK) Erk1 and Erk2 (Crepel et al. 1998). However, an inhibitory effect of increased tyrosine phosphorylation has also been reported (Doroshenko, 1998; Thoroed et al. 1999). Conflicting results also exist as to the role of protein kinase A (PKA), protein kinase C (PKC), or calmodulin kinase II depending on the cell preparation (Basavappa & Ellory, 1996; Strange et al. 1996; Kirk, 1997; Nilius et al. 1997; Okada, 1997). In several cell types, volume-sensitive Cl− currents can also be triggered by GTP-binding protein activation (Doroshenko et al. 1991; Nilius et al. 1997, 1999). Moreover, inhibition of either Rho protein (Tilly et al. 1996; Nilius et al. 1999) or Rho kinase (Nilius et al. 1999) affects activation of VSOACs, suggesting the involvement of small GTP-binding proteins of the Rho family in the regulation or the activation of the channel.

In the hypothalamic supraoptic nucleus (SON), taurine, which is prominently concentrated in glial cells (Decavel & Hatton, 1995), is released through volume-activated Cl− channels in response to hypotonic swelling (Deleuze et al. 1998). Release of taurine is highly sensitive to even minute, physiological changes in extracellular osmotic pressure (Deleuze et al. 1998). Such small stimuli apparently do not induce RVD, since the resulting release of taurine is sustained as long as the stimulus is applied (Deleuze et al. 1998). Rather, release of glial taurine induced by these weak decreases in osmolarity would contribute to the control of the electrical activity of SON neurones as part of the osmoregulation of vasopressin secretion (Hussy et al. 1997). As an effort to characterise the mechanism of activation of the volume-dependent channel carrying taurine efflux in SON, we studied the influence of tyrosine phosphorylation on the activation and osmosensitivity of taurine release from acutely isolated SON. Our results point to an important regulatory role of tyrosine phosphorylation on the osmosensitivity of volume-activated taurine-permeable Cl− channels, but with no direct implication in the cascade of events leading to activation of the efflux pathway. A preliminary account of these results has appeared in abstract form (Deleuze et al. 1999).

Tyrosine phosphorylation modulates the osmosensitivity of volume‐dependent taurine efflux from glial cells in the rat supraoptic nucleus

Ageing is known to induce a marked activation of astrocytes within various regions of the central nervous system. To date, the age-related factors responsible for these modifications are unknown.The neural lobe of the hypophysis (NL) is a particular brain region which does not contain neurons but does contain specialized astrocytes, called pituicytes, and numerous terminals of afferent axons, including (i) peptidergic neurohypophysial axons which terminate on the NL blood vessels, and (ii) axons containing both gamma amino-butyric acid (GABA) and dopamine (DA) which form contacts with pituicytes. Because evidence has recently been provided that GABA signalling mediates the morphological organization of astrocytes, the present study was designed to determine whether modifications of pituicytes during ageing were associated with modifications of the GABAergic axons innervating the NL. We show here that, in adult rats, GABA/DA axons form preferential synaptic-like contacts with pituicytes which express both GABA A and D2 dopamine receptors. We then show that, during ageing, pituicytes undergo dramatic modifications of their morphology, correlatively with marked modifications of the GABA/DA fibres innervating the NL. Lastly, in vitro experiments indicate that modifications of the morphology of pituicytes similar to those observed during ageing were obtained by incubating isolated NL of adult rats with a GABA A receptor agonist and/or a D2 dopamine receptor antagonist, whereas inverse modifications were observed when NL of aged rats were incubated with a GABA A receptor antagonist and a D2 dopamine receptor agonist. Taken together, these data suggest that the age-related morphological changes of pituicytes result from the alteration of the GABA/DAergic innervation of the NL.

Age-related modifications of the morphological organization of pituicytes are associated with alteration of the GABAergic and dopaminergic innervation afferent to the neurohypophysial lobe.

1. Taurine, prominently concentrated in glial cells in the supraoptic nucleus (SON), is probably involved in the inhibition of SON vasopressin neurones by peripheral hypotonic stimulus, via activation of neuronal glycine receptors. We report here the properties and origin of the osmolarity-dependent release of preloaded [3H]taurine from isolated whole SO nuclei. 2. Hyposmotic medium induced a rapid, reversible and dose-dependent increase in taurine release. Release showed a high sensitivity to osmotic change, with a significant enhancement with less than a 5% decrease in osmolarity. Hyperosmotic stimulus decreased basal release. 3. Evoked release was independent of extracellular Ca2+ and Na+, and was blocked by the Cl- channel blockers DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and DPC (N-phenylanthranilic acid), suggesting a diffusion process through volume-sensitive Cl- channels. 4. Evoked release was transient for large osmotic reductions (> or = 15%), probably reflecting regulatory volume decrease (RVD). However, it was sustained for smaller changes, suggesting that taurine release induced by physiological variations in osmolarity is not linked to RVD. 5. Basal and evoked release were strongly inhibited by an incubation of the tissue with the glia-specific toxin fluorocitrate, but were unaffected by a neurotoxic-treatment with NMDA, demonstrating the glial origin of the release of taurine in the SON. 6. The high osmosensitivity of taurine release suggests an important role in the osmoregulation of the SON function. These results strengthen the notion of an implication of taurine and glial cells in the regulation of the whole-body fluid balance through the modulation of vasopressin release.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7793.1998.463bt.x

Properties and glial origin of osmotic-dependent release of taurine from the rat supraoptic nucleus.

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Pharmacological characterization of volume-sensitive, taurine permeable anion channels in rat supraoptic glial cells

Tyrosine phosphorylation modulates the osmosensitivity of volume‐dependent taurine efflux from glial cells in the rat supraoptic nucleus

Age-related modifications of the morphological organization of pituicytes are associated with alteration of the GABAergic and dopaminergic innervation afferent to the neurohypophysial lobe.

Properties and glial origin of osmotic-dependent release of taurine from the rat supraoptic nucleus.