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Volume-regulated anion channel—a frenemy within the brain

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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is the contribution of VRAC to the release of the excitatory amino acid neurotransmitters glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field, the molecular nature of VRAC remained unknown until less than 2 years ago. Two pioneer publications identified VRAC as the heterohexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research.

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Abbreviations

CNS:

Central nervous system

DCPIB:

4-[(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid

GFP:

Green fluorescent protein

GPCR:

G-protein-coupled receptor

KCC:

K+,Cl− cotransporter

LRRC8:

Leucine-rich repeat-containing 8

NKCC:

Na+,K+,2Cl- cotransporter

NOS:

Nitric oxide synthase

NPPB:

5-Nitro-2-(3-phenylpropylamino)benzoic acid

RVD:

Regulatory volume decrease

RVI:

Regulatory volume increase

VRAC:

Volume-regulated anion channel

VSOAC:

Volume-sensitive organic osmolyte-anion channel

VSOR:

Volume-sensitive outwardly rectifying Cl− channel

YFP:

Yellow fluorescent protein

NMDA:

N-methyl-D-aspartate

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Acknowledgments

I am grateful to my colleagues, Dr. Richard W. Keller, Jr., and Alexandra L. Schober, for critical reading and helpful suggestions on the manuscript, as well as for help with figure preparation. The work in the author’s laboratory was supported by a grant from the National Institute for Neurological Disorders and Stroke (NS061953).

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    Alexander A. Mongin

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Frenemy (n.) is a portmanteau of “friend” and “enemy” that refers to one who pretends to be a friend but is actually an enemy. Frenemy may also denote the one who really is a friend but also a rival (Merriam-Webster Dictionary online accessed on 04/07/2015).

This article is published as a part of the special issue on “Molecular physiology of anion channels: dual function proteins and new structural motifs.”

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Mongin, A.A. Volume-regulated anion channel—a frenemy within the brain. Pflugers Arch - Eur J Physiol 468, 421–441 (2016). https://doi.org/10.1007/s00424-015-1765-6

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  • DOI: https://doi.org/10.1007/s00424-015-1765-6

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