Elsevier

Neuroscience

Volume 275, 5 September 2014, Pages 211-231
Neuroscience

Neuroscience Forefront Review
Characteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system

https://doi.org/10.1016/j.neuroscience.2014.06.015Get rights and content

Highlights

  • The VSOR anion channel is expressed in all types of cells in the CNS.

  • The channel produces a major anion flux during cell volume regulation.

  • The channel is permeable not only to Cl ions but also to amino acids.

  • Here we review and discuss the characteristics and roles of the channel in the CNS.

Abstract

Cell volume regulation (CVR) is essential for all types of cells in the central nervous system (CNS) to counteract cell volume changes that may be associated with neuronal activities or diseases and with osmosensing in the hypothalamus, to facilitate morphological changes during cell proliferation, differentiation and migration, and to execute apoptosis of cells. The regulation is attained by regulating the net influx or efflux of solutes and water across the plasma membrane. The volume-sensitive outwardly rectifying (VSOR) anion channel plays a major role in providing a pathway for anion flux during the regulation. The VSOR anion channel is permeable not only to Cl ions but also to amino acids like glutamate and taurine. This property confers a means of intercellular communications through the opening of the channel in the CNS. Thus exploring the roles of VSOR anion channels is crucial to understand the basic principles of cellular functions in the CNS. Here we review biophysical and pharmacological characteristics of the VSOR anion channel in the CNS, discuss its activation mechanisms and roles in the CNS reported so far, and give some perspectives on the next issues to be examined in the near future.

Introduction

Neuronal activities are generated by specific ion conductances increased in addition to the resting (background) conductance of the plasma membranes of individual neurons. The spikes of action potentials are produced by rapid opening of Na+ channels, whereas repolarization of the spikes is brought about by opening of K+ channels. The membrane potential is then shifted toward the equilibrium potentials of Na+ and K+, but never reaches them because of the presence of background conductances for other ions including Cl. Therefore, action potential generation results in the inflow of extracellular Na+ into and the release of intracellular K+ out of the neurons. These movements of Na+ and K+ are to be accompanied by the influx and efflux, respectively, of anions, especially Cl. Since the time course of Na+ and Cl influxes during spike generation is much faster than that of K+ and Cl effluxes during repolarization, high frequencies of neuronal activities tend to accumulate Na+ and Cl, and also water, in the neurons, resulting in cell swelling of somata and axons (Iwasa et al., 1980, Andrew and MacVicar, 1994, Tasaki, 1999, Takagi et al., 2002, Kim et al., 2007, Fields and Ni, 2010). Moreover, the K+ released from the neurons next facilitates the uptake of the K+ with Cl by adjacent astrocytes, causing the swelling of also the astrocytes (MacVicar et al., 2002). Their swelling causes the reduction in the extracellular space (Holthoff and Witte, 1996), which can indeed be detected during the neuronal activities in the brains of healthy human individuals (Darquié et al., 2001, Le Bihan et al., 2006). Both neurons and astrocytes therefore must cope with the activity-dependent cell swelling by the regulatory mechanisms of cell volume, otherwise the extracellular space may easily collapse and also the successive increases in intracranial pressure may cause life-threatening herniation of the brain. Indeed, in the brain edema and herniation induced by stroke or traumatic brain injury, the cell volume regulatory mechanisms are overwhelmed and disrupted by the action of excessive excitatory amino acids released from injured cells (Choi, 1988, Kimelberg, 2005, Okada et al., 2009a).

Cell volume regulation (CVR) is essential for all types of cells, and it works not only for the relief of cell swelling, but also for cell shape changes, cell proliferation, differentiation and migration, and apoptosis (Lang et al., 1998, Okada, 1998, Okada et al., 2001, Hoffmann et al., 2009). CVR is attained by regulating the net influx or efflux of solutes and water across the plasma membrane. Among the anion transport pathways involved in CVR, the volume-sensitive outwardly rectifying (VSOR) anion channel is known to be the most predominant one in most types of vertebrate cells, including those in the central nervous system (CNS; Strange et al., 1996, Nilius et al., 1997, Okada, 1997, Okada et al., 2009a, Okada et al., 2009b). The channel is typically activated in response to cell swelling, but it may be activated without swelling when certain types of stimulus or transmitter act on the cell (Liu et al., 2009, Okada et al., 2009a, Akita et al., 2011). The current through VSOR channels was first reported by two groups (Cahalan and Lewis, 1988, Hazama and Okada, 1988), and the properties of the VSOR channel have been studied extensively, especially in epithelial cells and in cell lines (Kubo and Okada, 1992, Strange et al., 1996, Nilius et al., 1997, Okada, 1997, Okada, 2006). They have also been examined in the CNS cells, mainly in isolated neurons (Leaney et al., 1997, Patel et al., 1998, Inoue et al., 2005, Inoue and Okada, 2007, Sato et al., 2011), astrocytes (Lascola and Kraig, 1996, Lascola et al., 1998, Crépel et al., 1998, Parkerson and Sontheimer, 2004, Kimelberg et al., 2006, Liu et al., 2006, Liu et al., 2009, Akita and Okada, 2011, Akita et al., 2011) and microglia (Schlichter et al., 1996, Schlichter et al., 2011, Ducharme et al., 2007, Harrigan et al., 2008, Svoboda et al., 2009). By contrast, the studies in slice or in vivo preparations are just emerging, including those from our group (Inoue and Okada, 2007, Inoue et al., 2007, Haskew-Layton et al., 2008, Zhang et al., 2008, Zhang et al., 2011). Since we have revealed quite diverse modes and roles of VSOR channel activation in the CNS cells (Liu et al., 2006, Liu et al., 2009, Inoue and Okada, 2007, Inoue et al., 2007, Akita and Okada, 2011, Akita et al., 2011, Sato et al., 2011), it is very important to investigate further the roles of the channel, in the context of not only the degree of cell swelling, but also the types of chemical transmitter and receptor involved and the interactions between neurons and glia, during the development, activities and diseases of the CNS.

Here we review the characteristics and roles of the VSOR anion channel in the CNS reported so far and give some perspectives on the next issues to be examined. Some technical limitations may arise from the fact that the molecular identity of the VSOR anion channel is not confirmed yet at this moment, although an essential molecular component of the channel was recently proposed (Qiu et al., 2014, Voss et al., 2014). Nevertheless, since the biophysical and pharmacological characteristics of the channel are established well (Strange et al., 1996, Nilius et al., 1997, Okada, 1997, Okada, 2006, Okada et al., 2009b), careful assessment of these characteristics in a given phenomenon may confirm the involvement of the channel in that phenomenon.

Section snippets

Mild outward rectification

The most characteristic feature of the current through VSOR anion channels is its mild outward rectification. When the inward and outward whole-cell Cl currents through VSOR channels are elicited by applying large symmetrical negative and positive membrane voltage (VM) steps (>±50 mV), respectively, from the reversal potential in a swollen CNS cell, the amplitude of the outward current is usually 2–3 times larger than that of the inward current (Fig. 1; see also examples in neurons and

Activation induced by cell swelling

The mechanism of swelling-induced activation of VSOR anion channels has long been debated (Nilius et al., 1997, Okada, 1997, Hoffmann et al., 2009, Okada et al., 2009a). Many different types of signaling cascade have been suggested to participate in the mechanism, but all of them proposed so far have been found to have only partial or permissive effects (Okada et al., 2009a). Among these, the contribution of intracellular Ca2+ signaling has been discussed frequently because cell swelling

Roles in neurons

Recovery of neuronal volume after activity-dependent swelling must be an important task for VSOR anion channels in neurons. Inhibitors of VSOR channels certainly inhibit the RVD after the swelling elicited by hypotonic shock in neurons (Inoue et al., 2005, Sato et al., 2011). The speed of RVD, however, seems to be variable between different types of neuron. Overall, a larger size of neurons tends to show a slower rate of RVD. For instance, the somata of cerebellar granule neurons, the smallest

Perspective

In summary, the well-established roles of VSOR anion channels in the CNS are the induction of RVD or apoptosis and the release of glutamate, especially during brain injury. These roles of the channel are based on the fact that the most effective stimuli for VSOR channel activation are cell swelling and apoptotic signaling. Indeed, the degree and effects of VSOR channel activation during brain injury are so clear and strong that the blockade of VSOR channels drastically reduces neuronal damage

Conclusion

Based on the diverse modes of activation of VSOR anion channels in the CNS reported so far, VSOR channel activity is undoubtedly involved, more or less, in all types of cells throughout the lifespan of the CNS, including its development, mature activity and diseases. However, the roles of the channel, especially during the development and the physiological activity of the CNS, have not been thoroughly elucidated yet. Compared to the situations during brain injury, in which VSOR channel activity

Acknowledgments

We are grateful to all members of Department of Cell Physiology in National Institute for Physiological Sciences and Department of Neurophysiology in Hamamatsu University School of Medicine for fruitful discussions and suggestions on this work. This work was supported by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (21790216 and 23612008 to T.A. and 21249010 to Y.O.) and from the Ministry of Education, Culture, Sports, Science, and Technology – Japan (

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    Present address: Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.

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