Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC)

James Osei-Owusu, Junhua Yang, Maria del Carmen Vitery, Zhaozhu Qiu

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The Volume-Regulated Anion Channel (VRAC) is activated by cell swelling and plays a key role in cell volume regulation. VRAC is ubiquitously expressed in vertebrate cells and also implicated in many other physiological and cellular processes including fluid secretion, glutamate release, membrane potential regulation, cell proliferation, migration, and apoptosis. Although its biophysical properties have been well characterized, the molecular identity of VRAC remained a mystery for almost three decades. The field was transformed by recent discoveries showing that the leucine-rich repeat-containing protein 8A (LRRC8A, also named SWELL1) and its four other homologs form heteromeric VRAC channels. The composition of LRRC8 subunits determines channel properties and substrate selectivity of a large variety of different VRACs. Incorporating purified SWELL1-containing protein complexes into lipid bilayers is sufficient to reconstitute channel activities, a finding that supports the decrease in intracellular ionic strength as the mechanism of VRAC activation during cell swelling. Characterization of Swell1 knockout mice uncovers the important role of VRAC in T cell development, pancreatic β-cell glucose-stimulated insulin secretion, and adipocyte metabolic function. The ability to permeate organic osmolytes and metabolites is a major feature of VRAC. The list of VRAC substrates is expected to grow, now also including some cancer drugs and antibiotics even under non-cell swelling conditions. Therefore, a critical role of VRAC in drug resistance and cell–cell communication is emerging. This review summarizes the exciting recent progress on the structure-function relationship and physiology of VRAC and discusses key future questions to be solved.

Original languageEnglish (US)
Title of host publicationCurrent Topics in Membranes
EditorsIrena Levitane, Eric Delpire, Hector Rasgado-Flores
PublisherAcademic Press Inc.
Pages177-203
Number of pages27
ISBN (Print)9780128154564
DOIs
StatePublished - Jan 1 2018

Publication series

NameCurrent Topics in Membranes
Volume81
ISSN (Print)1063-5823

Keywords

  • Astrocyte
  • Cell swelling
  • Drug uptake
  • Glutamate release
  • Ion channel
  • Ionic strength
  • LRRC8
  • LRRC8A
  • SWELL1
  • Volume-regulated anion channel

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Osei-Owusu, J., Yang, J., Vitery, M. D. C., & Qiu, Z. (2018). Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC). In I. Levitane, E. Delpire, & H. Rasgado-Flores (Eds.), Current Topics in Membranes (pp. 177-203). (Current Topics in Membranes; Vol. 81). Academic Press Inc.. https://doi.org/10.1016/bs.ctm.2018.07.005