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VRACs and other ion channels and transporters in the regulation of cell volume and beyond

Nature Reviews Molecular Cell Biology volume 17, pages 293–307 (2016)Cite this article

Subjects

Key Points

  • Cells need to adjust their volume in response to external osmotic stress, but also during the execution of cellular functions. These adjustments include changes in metabolism, transepithelial transport, cell division, growth, migration and programmed cell death.

  • Cell volume regulation uses the generation of osmotic gradients across the plasma membrane. These gradients drive water through the membrane, which is facilitated by specialized water channels.

  • Short-term volume regulation depends on plasma membrane channels or transporters that accumulate or release cellular osmolytes — mainly potassium, sodium and chloride, and organic osmolytes such as taurine, glutamate and inositol — in response to cell shrinkage and swelling, respectively. The underlying volume sensors and signalling cascades are complex and generally remain poorly understood.

  • Most volume-regulatory plasma membrane transporters have additional important cellular and organismal functions, linking cell volume to processes such as regulation of cytoplasmic pH, transepithelial transport and the release of signalling molecules.

  • Key players in cell volume regulation are the volume-regulated anion channels (VRACs), which have only recently been discovered to be composed of LRRC8 heteromers. Depending on the particular subunit composition, VRACs not only transport chloride, but also organic osmolytes and even clinically important anticancer drugs, and they have a role in apoptosis.

  • VRAC-mediated release of taurine, glutamate and other metabolites may activate neurotransmitter receptors in the nervous system, suggesting a role for VRACs in astrocyte–neuron communication, systemic volume regulation and pathologies such as stroke.

Abstract

Cells need to regulate their volume to counteract osmotic swelling or shrinkage, as well as during cell division, growth, migration and cell death. Mammalian cells adjust their volume by transporting potassium, sodium, chloride and small organic osmolytes using plasma membrane channels and transporters. This generates osmotic gradients, which drive water in and out of cells. Key players in this process are volume-regulated anion channels (VRACs), the composition of which has recently been identified and shown to encompass LRRC8 heteromers. VRACs also transport metabolites and drugs and function in extracellular signal transduction, apoptosis and anticancer drug resistance.

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Figure 1: Plasma membrane channels and transporters involved in cell volume regulation.
Figure 2: Properties of volume-regulated anion channels (VRACs).
Figure 3: Some proposed roles of volume-regulated anion channels (VRACs) beyond volume regulation.

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Acknowledgements

The author thanks Rosa Planells-Cases for help with figures, and members of his laboratory for critical reading of the manuscript. Work on VRACs is supported in the author's laboratory by the European Research Council Advanced Grant (FP/2007-2013) 294435 'Cytovolion' and the Deutsche Forschungsgemeinschaft (Exc 257 'Neurocure' and JE164/12).

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  1. Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany

    Thomas J. Jentsch

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Methods to measure cell volume (PDF 185 kb)

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Glossary

Osmolytes

Dissolved substances that contribute to osmolarity; in biology, the term mainly refers to substances playing a significant part in osmoregulation. Osmolytes can be electrically charged or neutral, as only the concentration of particles matters.

Hypo- or hypertonic

Condition in which the concentration of osmolytes that are not freely membrane permeable is lower or higher, respectively, on the reference side of a membrane, compared with the other side. This concentration difference creates an osmotic pressure.

Osmolarity

Concentration of solute particles per kg of solution, irrespective of their ability to freely cross a given membrane.

Depolarization

A change in the resting voltage of cells (−40 to −80 mV inside versus outside) to more positive values. A change to more negative potentials is called hyperpolarization.

Electrochemical gradients

The passive, diffusive transport of an ion across a membrane through a channel is driven not only by the concentration difference of that ion, but also by the voltage across that membrane. The driving force is given by the difference in electrochemical potential according to the Nernst equation, for example, for a singly charged anion A− by EA = (RT/F)*ln([A−]i / [A−]o), with R being the gas constant, T the absolute temperature, F Faraday's constant, and [A−]i the intracellular and [A−]o the extracellular concentration of the anion.

Donnan effects

Effects on the voltage and concentration differences of charged particles across a semipermeable membrane, caused by the impermeability of the membrane to one ionic species.

GABA (γ-aminobutyric acid) type A receptor

(GABAA receptor). A pentameric anion channel that is opened by the binding of GABA. Channels of this type mediate fast synaptic inhibition in the nervous system by allowing a passive influx of Cl− which hyperpolarizes the membrane. This requires a low intracellular Cl− concentration, as found in most adult neurons.

Glycine receptor

A pentameric anion channel that inhibits neuronal excitability by mediating a hyperpolarizing Cl− influx upon extracellular binding of the amino acid and neurotransmitter glycine.

Conductance

Electrical conductance is the inverse of electrical resistance. For instance, the K+ conductance of a biological membrane is a quantitative measure of the current mediated by K+ channels divided by the driving force (given by potential and concentration differences across the membrane). It depends on the number of open K+ channels and how readily they allow the passage of K+ ions.

Outward rectification

A channel is called outwardly rectifying if its currents are larger at inside-positive than at inside-negative voltages, which corresponds to an outward transport of positive charge. For anion channels this corresponds to an inward transport of anions.

Channel inactivation

The spontaneous closure of a channel at constant voltage.

Astrocytes

A major class of glial (non-neuronal) cells in the central nervous system, which have important functions, for instance, in buffering extracellular ion concentrations, in removal of neurotransmitters and in neuronal metabolism.

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Jentsch, T. VRACs and other ion channels and transporters in the regulation of cell volume and beyond. Nat Rev Mol Cell Biol 17, 293–307 (2016). https://doi.org/10.1038/nrm.2016.29

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