Volume-regulated anion channel

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Basic role of VRAC in RVD and Cell Apoptosis. This model is simplistic as it does not account for different LRRC8 protein subunits that make up the VRACs. It has been determined by Planells-Cases et al. that different subunit composition allows for specificity of VRACs (2015). This shown process is for RVD, but VRAC is also active in the observed cell shrinkage that occurs before apoptosis through the same release of anions and organic osmolytes. VRAC.png
Basic role of VRAC in RVD and Cell Apoptosis. This model is simplistic as it does not account for different LRRC8 protein subunits that make up the VRACs. It has been determined by Planells-Cases et al. that different subunit composition allows for specificity of VRACs (2015). This shown process is for RVD, but VRAC is also active in the observed cell shrinkage that occurs before apoptosis through the same release of anions and organic osmolytes.

Volume-regulated anion channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, [1] and that is not the only function these channels have been linked to. Some research has also suggested that VRACs may be water-permeable as well. [2]

Contents

The regulation of cell volume is necessary not only as a prevention against swelling or shrinkage caused by a change in the cell's environment, but also throughout all stages of a cell's life. The changing of a cell's volume, whether it be swelling or shrinkage, generally occurs without major changes, such as exocytic insertion or endocytic retrieval of the plasma membrane. [1] Instead, volume regulation mostly occurs through the transport of potassium, sodium, chloride, and organic osmolytes across the membrane. [1] The ramifications of cells not being able to regulate their volume size in relation to their environments are great as swelling leads to lysis, and shrinking eventually leads from dehydration to apoptosis. [3] The specific role that VRACs play in the regulation of cell volume specifically is regulatory volume decrease (RVD) of cells. [1]

Research of VRACs has led some to conclude that they are widely expressed in mammalian cells and that they may even be ubiquitously expressed. [4] VRACs have also been shown to participate in fundamental cellular processes other than basic volume regulation, such as cell proliferation, migration, and apoptosis. [5] [6]

Structure and mechanism

Although the scientific community has known about VRACs for a long time, [7] it was only recently discovered what the molecular composition of the channels is. They are composed of LRRC8 protein heteromers, of which there are five variations. [8] However, the specific composition of LRRC8A, LRRC8B, LRRC8C, LRRC8D, and LRRC8E necessary for a properly functioning VRAC are unknown. LRRC8A alone can form a hexameric VRAC, for which the cyro-EM structure has been determined in its mice and human versions. [9] [10] [11]

Research has also shown that variations in the composition of the subunits leads to variations in the ability of VRACs to transport certain metabolites. [12] For instance, the subunit LRRC8D being involved in the composition of VRAC has been highly associated with the transport of taurine along with specific anti-cancer drugs. [12] Because of experiments like this, we know that it is likely that LRRC8 proteins create the VRAC pore as well.

As for a mechanism for VRACs, recent research has suggested that they are activated when there is a reduction of intracellular ionic strength, which implies that VRACs may also act as sensors as well as affecters of cell volume regulation. [13] However, researchers have not been able to find any intracellular signaling mechanisms that play a dominant role in VRAC activation. [3]

The transmembrane portion of LRRC8 proteins are similar to those in Pannexins. [14]

Roles in neurons

VRACs are crucial for transport of not only chloride, but also taurine, glutamate, and aspartate. [3] [1] These organic osmolytes are important for more than cellular volume regulation as they are also very crucial for extracellular signaling. To set the stage for VRACs role in extracellular signaling, we must discuss some consequences that the release of glutamate and taurine from VRACs has on surrounding neurons respectively.

For glutamate, when excitatory neurotransmitters are released and activates channels on surrounding neurons, it results in overactive depolarization, and increase in calcium ions, and eventually cellular apoptosis. [3] This is generally called excitotoxicity, and it normally results in neuronal swelling. [6] VRACs' release of organic osmolytes as a response to this swelling and influx of ions most likely aids in the prevention of the neuron from bursting, as the release of inorganic compounds from a cell has only been associated with a cellular volume decrease of about 20-30%. [15] Yet, in addition to the prevention of lysis for the neuron, the release of taurine and glutamate will also continue to propagate the excitotoxicity effect on neighboring neurons. The most relevant cells to study regarding VRACs role and reaction to excitotoxicity are astrocytes. This is because of their role as supporters of neuronal communication in the brain, the fact that they have been proven to contain VRACs, and the fact that they have been found in a swollen condition in response to pathologies regarding excitotoxicity. [3] As we have stated, the increase of stimulation on a neuron results in excitotoxicity, and glutamate is one of the neurotransmitters that in excess could cause this neuronal response. There are many pathologies attributed to this cellular response including stroke and hypoglycemia among others. [16] As an example, a few studies have found that astrocytes cellular VRAC activation might be associated with stroke-related increases in substances like ATP. [17] Experiments have found that VRAC inhibitors were able to decrease the stroke-related release of excitatory neurotransmitters in the brain; [6] which means that VRACs are likely activated by the increase of cellular ATP and other molecules in astrocytes, and the release of glutamate by these cells causes the neurons around them to become depolarized, increase their calcium ion concentration, and undergo apoptosis. [6]

The other organic osmolyte associated with VRACs, taurine, also has many extracellular signaling functions. Specifically, it is thought that the release of taurine from glia by VRACs is linked to systemic volume regulation in the osmosensing supraoptical nucleus (SON). [18] At first, researchers thought that neurons found in SON were not able to undergo RVD, but it was later found that they do eventually develop a chloride ion current after a certain amount of time. [18] Astrocytes were again studied in relation to this discovery, and they found that the cells readily respond to a hypertonic environment by releasing taurine through VRAC-like channels. [18] In turn, the taurine activates glycine receptor chloride channels on neighboring SON neurons, which causes them to hyperpolarize. [18] Since the SON neurons shrink and depolarize in a hypertonic environment, [18] this interaction between the astrocytes acts as an inhibitor of the secretion of vasopressin by SON.

Based on these studies conducted on VRACs role in both excitotoxicity conditions and the regulation of the osmosensing supraoptical nucleus (SON), there are large implications for the actual influence this channel has on everyday neuronal activity. It is likely that VRACs play a lot of major parts in neuronal regulation; however, it is difficult for researchers to narrow down the scope of their effects. Another important aspect of neurons to keep in mind is that potassium, chloride cotransporters (KCCs) are other proteins that are also part of the RVD process and are activated when cells undergo swelling. [3] [1] This is important to keep in mind because VRACs are not the only molecules present that aid in cell volume regulation, and recent research has shown that the likelihood that these two channels work cooperatively is high. [3]

Medical connections

In addition to the connections presented in the discussion of VRACs’ many roles in neurons, research has shown that cell shrinkage largely precedes cell death (known as AVD – apoptotic volume decrease), [19] and there has been research that has shown that VRACs plays a role in this process. [5] It is likely that cell shrinkage inhibition is linked with inhibitors of VRACs or with the general disruption of LRRC8 proteins. [5] [19] This inhibition or disruption ultimately leads to suppressed drug-induced apoptosis. Therefore, VRACs could play a role in drug resistance in certain types of cancer.

Related Research Articles

Excitatory synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron often making numerous connections with other cells. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Excitotoxicity Process that kills nerve cells

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or N-methyl-D-aspartic acid (NMDA) become pathologically high resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter glutamate significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biologic life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival to otherwise toxic levels of glutamate.

Astrogliosis Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

Glutamate receptor

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

KCNB1

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

Chloride potassium symporter 5 Protein-coding gene in the species Homo sapiens

Potassium-chloride transporter member 5 is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Potassium-chloride transporter member 5 is also known by the names: KCC2 for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans.

LRRC8D

Leucine-rich repeat-containing protein 8D is a protein that in humans is encoded by the LRRC8D gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8E, is a subunit of the heteromer protein Volume-Regulated Anion Channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.

LRRC8A

Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8B, LRRC8C, LRRC8D, and LRRC8E, is a subunit of the heteromer protein volume-regulated anion channel (VRAC). (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.

Quinolinic acid Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to nicotine.

LRRC8E

Leucine-rich repeat-containing protein 8E is a protein that in humans is encoded by the LRRC8E gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8D, is sometimes a subunit of the heteromer protein volume-regulated anion channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.

Alzheimer type II astrocyte

The Alzheimer type II astrocyte is thought to be a pathological type of cell in the brain; however, its exact pathology remains unknown. Like other astrocytes, it is a non-neuronal glial cell. It's mainly seen in diseases that cause increased levels of ammonia (hyperammonemia), such as chronic liver disease and Wilson's disease.

GABA transporters (Gamma-Aminobutyric acid transporters) belong to the family of neurotransmitters known as sodium symporters, also known as solute carrier 6 (SLC6). These are large family of neurotransmitter which are Na+ concentration dependent. They are found in various regions of the brain in different cell types, such as neurons and astrocytes.

SGK1

Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene.

Glutamate (neurotransmitter) Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate refers to the anion of glutamic acid in its role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

Leucine-rich repeat-containing protein 8B is a protein that in humans is encoded by the LRRC8B gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8C, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein volume-regulated anion channel (VRAC). VRACs are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.

LRRC8C

Leucine-rich repeat-containing protein 8C is a protein that in humans is encoded by the LRRC8C gene. Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel. Volume-Regulated Anion Channels (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane, and that is not the only function these channels have been linked to.

Changjoon Justin Lee

Changjoon Justin Lee is a neuroscientist specializing in the field of glioscience. He served as the Director of Center for Neuroscience at the Korea Institute of Science and Technology and later founded the WCI Center for Functional Connectomics as part of the World Class Institute Program. In 2015, he established the Center for Glia-Neuron Interaction before becoming co-director of the IBS Center for Cognition and Sociality and head of the Cognitive Glioscience Group in 2018. He has been on the editorial boards of the journals Molecular Brain and Molecular Pain and is a chief editor of Experimental Neurobiology.

References

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