Neuroscience Forefront ReviewCharacteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system
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 (
References (233)
- et al.
Purinergic signalling in the nervous system: an overview
Trends Neurosci
(2009) - et al.
Potential sources of intrinsic optical signals imaged in live brain slices
Methods
(1999) - et al.
Imaging cell volume changes and neuronal excitation in the hippocampal slice
Neuroscience
(1994) - et al.
Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism
Prog Neurobiol
(2005) - et al.
Purinergic signalling: from normal behaviour to pathological brain function
Prog Neurobiol
(2011) Glutamate neurotoxicity and diseases of the nervous system
Neuron
(1988)Glutamate uptake
Prog Neurobiol
(2001)- et al.
Tamoxifen activates smooth muscle BK channels through the regulatory β1 subunit
J Biol Chem
(2001) - et al.
Green fluorescent protein-based halide indicators with improved chloride and iodide affinities
FEBS Lett
(2001) - et al.
Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling
Biochim Biophys Acta
(2014)
Cell volume regulation in response to hypotonicity is impaired in HeLa cells expressing a protein kinase Cα mutant lacking kinase activity
J Biol Chem
Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure
Prog Neurobiol
Volume-sensitive outwardly rectifying chloride channels are involved in oxidative stress-induced apoptosis of mesangial cells
Biochem Biophys Res Commun
A mechanical spike accompanies the action potential in mammalian nerve terminals
Biophys J
Taurine enhances volume regulation in hippocampal slices swollen osmotically
Neuroscience
LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication
Bioessays
Pharmacological comparison of swelling-activated excitatory amino acid release and Cl− currents in cultured rat astrocytes
J Physiol
Upregulation of swelling-activated Cl− channel sensitivity to cell volume by activation of EGF receptors in murine mammary cells
J Physiol
Expression and modulation of an NADPH oxidase in mammalian astrocytes
J Neurosci
Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation
J Neurosci
Ca2+ nanodomain-mediated component of swelling-induced volume-sensitive outwardly rectifying anion current triggered by autocrine action of ATP in mouse astrocytes
Cell Physiol Biochem
Regulation of bradykinin-induced activation of volume-sensitive outwardly rectifying anion channels by Ca2+ nanodomains in mouse astrocytes
J Physiol
Taurine interaction with neurotransmitter receptors in the CNS: an update
Neurochem Res
The molecular basis of water transport in the brain
Nat Rev Neurosci
Cation regulation of anion current activated by cell swelling in two types of human epithelial cancer cells
J Physiol
Down-regulation of volume-sensitive Cl− channels by CFTR is mediated by the second nucleotide-binding domain
Pflügers Arch Eur J Physiol
Involvements of the ABC protein ABCF2 and α-actinin-4 in regulation of cell volume and anion channels in human epithelial cells
J Cell Physiol
Physiological evidence that pyramidal neurons lack functional water channels
Cereb Cortex
Chloride current activated by hypotonicity in cultured human astrocytoma cells
Exp Physiol
Anion channels for amino acids in MDCK cells
Am J Physiol Cell Physiol
Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function
J Neurochem
Imaging spreading depression and associated intracellular calcium waves in brain slices
J Neurosci
Glutamate release through volume-activated channels during spreading depression
J Neurosci
Volume-sensitive chloride channels blocked by neuroprotective drugs in human glial cells (U-138MG)
Glia
The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology
Physiol Rev
Macula densa cell signaling involves ATP release through a maxi anion channel
Proc Natl Acad Sci U S A
Carbenoxolone inhibits volume-regulated anion conductance in cultured rat cortical astroglia
Channels
Chloride current activated by swelling in retinal pigment epithelium cells
Am J Physiol Cell Physiol
DCPIB, the proposed selective blocker of volume-regulated anion channels, inhibits several glutamate transport pathways in glial cells
Mol Pharmacol
NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation
Nat Neurosci
Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl− current elicited by beta1 integrin stretch in rabbit ventricular myocytes
J Gen Physiol
EGFR kinase regulates volume-sensitive chloride current elicited by integrin stretch via PI-3K and NADPH oxidase in ventricular myocytes
J Gen Physiol
Taurine activates delayed rectifier Kv channels via a metabotropic pathway in retinal neurons
J Physiol
Role of potassium and chloride channels in volume regulation by T lymphocytes
Soc Gen Physiol Ser
TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity
Science
Swelling- and cAMP-activated Cl− currents in isolated rat carotid body type I cells
J Physiol
RhoA exerts a permissive effect on volume-regulated anion channels in vascular endothelial cells
Am J Physiol Cell Physiol
Non-equilibration of hydrostatic pressure in blebbing cells
Nature
Riluzole, neuroprotection and amyotrophic lateral sclerosis
Curr Med Chem
Taurine release by astrocytes modulates osmosensitive glycine receptor tone and excitability in the adult supraoptic nucleus
J Neurosci
Cited by (0)
- †
Present address: Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.