Volume regulated chloride channels (VRAC) | Ion channels

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Volume regulated chloride channels (VRAC)

Volume regulated chloride channels (VRAC) C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Volume activated chloride channels (also termed VSOAC, volume-sensitive organic osmolyte/anion channel; VRC, volume regulated channel and VSOR, volume expansion-sensing outwardly rectifying anion channel) participate in regulatory volume decrease (RVD) in response to cell swelling. VRAC may also be important for several other processes including the regulation of membrane excitability, transcellular Cl^- transport, angiogenesis, cell proliferation, necrosis, apoptosis, glutamate release from astrocytes, insulin (INS, P01308) release from pancreatic β cells and resistance to the anti-cancer drug, cisplatin (reviewed by [1-4]). VRAC may not be a single entity, but may instead represent a number of different channels that are expressed to a variable extent in different tissues and are differentially activated by cell swelling. In addition to ClC-3 expression products (see above) several former VRAC candidates including MDR1 (ABCB1 P-glycoprotein), Icln, Band 3 anion exchanger and phospholemman are also no longer considered likely to fulfil this function (see reviews [3,5]).

Channels and Subunits

710

VRAC C Show summary »« Hide summary

Target Id

710

Nomenclature

VRAC

Previous and unofficial names

VRAC (volume regulated anion channel) | VRC (volume regulated channel) | VSOAC (volume-sensitive organic osmolyte/anion channel) | VSOR (volume expansion-sensing outwardly rectifying anion channel)

Activators

GTPγS

Endogenous channel blockers

intracellular Mg²⁺

arachidonic acid

Channel blockers

tamoxifen

quinidine

quinine

mibefradil

1,9-dideoxyforskolin

9-anthroic acid

carbenoxolone

clomiphene

DCPIB

diBA-(5)-C4

DIDS

gossypol

IAA-94

mefloquine

nafoxidine

nordihydroguiaretic acid

NPPB

NS3728

Functional characteristics

γ = 10-20 pS (negative potentials), 50-90 pS (positive potentials); permeability sequence SCN > I > NO₃^- >Br^- > Cl^- > F^- > gluconate; outward rectification due to voltage dependence of γ; inactivates at positive potentials in many, but not all, cell types; time dependent inactivation at positive potentials; intracellular ionic strength modulates sensitivity to cell swelling and rate of channel activation; rate of swelling-induced activation is modulated by intracellular ATP concentration; ATP dependence is independent of hydrolysis and modulated by rate of cell swelling; inhibited by increased intracellular free Mg²⁺ concentration; swelling induced activation of several intracellular signalling cascades may be permissive of, but not essential to, the activation of VRAC including: the Rho-Rho kinase-MLCK; Ras-Raf-MEK-ERK; PIK3-NOX-H₂O₂ and Src-PLCγ-Ca²⁺ pathways; regulation by PKCα required for optimal activity; cholesterol depletion enhances activity; activated by direct stretch of β1-integrin

Comment

VRAC is also activated by cell swelling and low intracellular ionic strength. VRAC is also blocked by chromones, extracellular nucleotides and nucleoside analogues

Comments

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References

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1. Best L, Brown PD, Sener A, Malaisse WJ. (2010) Electrical activity in pancreatic islet cells: The VRAC hypothesis. Islets, 2 (2): 59-64. [PMID:21099297]

2. Mulligan SJ, MacVicar BA. (2006) VRACs CARVe a path for novel mechanisms of communication in the CNS. Sci STKE, 2006 (357): pe42. [PMID:17047222]

3. Nilius B, Droogmans G. (2003) Amazing chloride channels: an overview. Acta Physiol Scand, 177 (2): 119-47. [PMID:12558550]

4. Okada Y, Sato K, Numata T. (2009) Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel. J Physiol (Lond.), 587 (Pt 10): 2141-9. [PMID:19171657]

5. Sardini A, Amey JS, Weylandt KH, Nobles M, Valverde MA, Higgins CF. (2003) Cell volume regulation and swelling-activated chloride channels. Biochim Biophys Acta, 1618 (2): 153-62. [PMID:14729152]

How to cite this family page

Database page citation:

Volume regulated chloride channels (VRAC). Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=132.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.