Human ClC-3 Is Not the Swelling-activated Chloride Channel Involved in Cell Volume Regulation

Weylandt, Karsten H.; Valverde, Miguel A.; Nobles, Muriel; Raguz, Selina; Amey, Joanna S.; Dı́az, Mario; Nastrucci, Candida; Higgins, Christopher F.; Sardini, Alessandro

doi:10.1074/jbc.m011667200

Cited by 90 publications

(84 citation statements)

References 37 publications

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“…Investigation into the expression levels of both mRNA and protein in various tissues has led to conflicting results (24,33,36,60). Expression of cloned ClC-3 either from human (32,36,43), rat (24,33,34), or guinea pig (16,27,28) has led to differing biophysical and pharmacological properties or the inability to detect expressed ClC-3 chloride currents (36,37,61). There is also contradictory data as to whether the protein is an intracellular channel (35) or plasma membrane channel (33,43).…”

Section: Discussionmentioning

confidence: 99%

“…Since ClC-3 was first cloned and expressed by Kawasaki et al in 1994, contradictory data has been reported for the functional expression of the ClC-3 chloride channel. Investigation into the expression levels of both mRNA and protein in various tissues has led to conflicting results (24,33,36,60). Expression of cloned ClC-3 either from human (32,36,43), rat (24,33,34), or guinea pig (16,27,28) has led to differing biophysical and pharmacological properties or the inability to detect expressed ClC-3 chloride currents (36,37,61).…”

Section: Discussionmentioning

confidence: 99%

“…Also, a polyclonal anti-ClC-3 antibody (Ab) was shown to functionally inhibit native VSOACs in guinea pig cardiac cells, canine pulmonary arterial smooth muscle cells, and Xenopus laevis oocytes (28). Although the ClC-3 hypothesis has received additional experimental support from other laboratories, (29 -32) its role as a volume sensitive chloride channel has recently become controversial (33)(34)(35)(36).…”

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confidence: 99%

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ClC-3 Is a Fundamental Molecular Component of Volume-sensitive Outwardly Rectifying Cl− Channels and Volume Regulation in HeLa Cells and Xenopus laevis Oocytes

Hermoso

Satterwhite²,

Andrade

et al. 2002

Journal of Biological Chemistry

106

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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ClC-3 Is a Fundamental Molecular Component of Volume-sensitive Outwardly Rectifying Cl− Channels and Volume Regulation in HeLa Cells and Xenopus laevis Oocytes

Hermoso

Satterwhite²,

Andrade

et al. 2002

Journal of Biological Chemistry

106

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“…Cl Ϫ currents were measured in the whole cell recording mode of the patch-clamp technique as described previously (46). Cells were plated in 35-mm plastic dishes coated with fibronectinbased solution (see above) and mounted on the stage of an inverted Leica DMIL microscope.…”

Section: Methodsmentioning

confidence: 99%

Extracellular acidification elicits a chloride current that shares characteristics with I_Cl(swell)

Nobles

Higgins

Sardini

2004

American Journal of Physiology-Cell Physiology

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Nobles, Muriel, Christopher F. Higgins, and Alessandro Sardini. Extracellular acidification elicits a chloride current that shares characteristics with ICl(swell). Am J Physiol Cell Physiol 287: C1426 -C1435, 2004. First published August 11, 2004 doi:10.1152/ ajpcell.00549.2002-A Cl Ϫ current activated by extracellular acidification, ICl(pHac), has been characterized in various mammalian cell types. Many of the properties of ICl(pHac) are similar to those of the cell swelling-activated Cl Ϫ current ICl(swell): ion selectivity (I Ϫ Ͼ Br Ϫ Ͼ Cl Ϫ Ͼ F Ϫ ), pharmacology [ICl(pHac) is inhibited by 4,4Ј-diisothiocyanostilbene-2,2Ј-disulfonic acid (DIDS), 1,9-dideoxyforskolin (DDFSK), diphenylamine-2-carboxylic acid (DPC), and niflumic acid], lack of dependence on intra-or extracellular Ca 2ϩ , and presence in all cell types tested. ICl(pHac) differs from ICl(swell) in three aspects: 1) its rate of activation and inactivation is very much more rapid, currents reaching a maximum in seconds rather than minutes; 2) it exhibits a slow voltage-dependent activation in contrast to the fast voltage-dependent activation and time-and voltage-dependent inactivation observed for ICl(swell); and 3) it shows a more pronounced outward rectification. Despite these differences, study of the transition between the two currents strongly suggests that ICl(swell) and ICl(pHac) are related and that extracellular acidification reflects a novel stimulus for activating I Cl(swell) that, additionally, alters the biophysical properties of the channel.cell swelling-activated chloride current; patch clamp; pH A CHLORIDE CURRENT ACTIVATED by cell swelling (I Cl(swell) ) has been characterized in many different cell types (for review see Refs. 26 and 37), and it is thought to play a role in regulatory cell volume decrease (RVD) in response to hypotonicity. I Cl(swell) exhibits outward rectification, fast voltage-dependent activation, and time-and voltage-dependent inactivation at potentials more positive than ϩ40 mV. The relative anion selectivity for the swelling-activated Cl Ϫ channel is SCN Ϫ Ͼ I Ϫ Ͼ Br Ϫ Ͼ Cl Ϫ Ͼ F Ϫ Ͼ gluconate; this sequence is referred to as "Eisenman sequence I" and indicates a weak interaction between the channel pore and the permeation anion. A number of different substances, including the stilbene derivative 4,4Ј-diisothiocyanostilbene-2,2Ј-disulfonic acid (DIDS) (9, 35), the anti-inflammatory drug niflumic acid (20), the antiestrogen drug tamoxifen (43), diphenylamine-2-carboxylic acid (DPC) (22), and 1,9-dideoxyforskolin (DDFSK) (9), inhibit I Cl(swell) . Furthermore I Cl(swell) is insensitive to changes in calcium concentrations (33). Despite much effort and several candidates, P-glycoprotein (P-gp) (42), pICln (30) and ClC-3 (12), none has stood the test of time, and the molecular identity of the channel responsible for I Cl(swell) and its mechanism of activation remain unknown. Extracellular acidification has been reported to both activate and inhibit anion channel activities in different cell types. Extracellular...

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“…1,2 In the 1990s, several proteins, including P-glycoprotein, pI cln , and ClC-3, were proposed as molecular identities of VSOR, [3][4][5] but none of them has survived scrutiny. [6][7][8][9][10][11][12] In 2014, 2 research groups independently reported that the leucine-rich repeat containing 8A (LRRC8A), which has 4 transmembrane domains and a leucine-rich repeat (LRR) domain at the C-terminus, is a core factor of VSOR in human cells. 13,14 They reported in common that knockdown of LRRC8A diminished endogenous VSOR currents in human cells, and such reduced currents could be rescued by introduction of exogenous LRRC8A, but overexpression of LRRC8A alone in normal cells paradoxically reduced endogenous VSOR currents.…”

Section: Introductionmentioning

confidence: 99%

Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)

et al. 2016

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The broadly expressed volume-sensitive outwardly rectifying anion channel (VSOR, also called VRAC) plays essential roles in cell survival and death. Recent findings have suggested that LRRC8A is a core component of VSOR in human cells. In the present study, VSOR currents were found to be largely reduced by siRNA against LRRC8A in mouse C127 cells as well. In contrast, LRRC8A knockdown never affected activities of 4 other types of anion channel activated by acid, Ca 2C , patch excision or cAMP. While cisplatin-resistant KCP-4 cells poorly expressed endogenous VSOR activity, molecular expression levels of LRRC8A, LRRC8D and LRRC8E were indistinguishable between VSOR-deficient KCP-4 cells and the parental VSOR-rich KB cells. Furthermore, overexpression of LRRC8A alone or together with LRRC8D or LRRC8E in KCP-4 cells failed to restore VSOR activity. These results show that deficiency of VSOR currents in KCP-4 cells is not due to insufficient expression of the LRRC8A/D/ E gene, suggesting an essential involvement of some other factor(s), and indicate that further study is required to better understand the complexities of the molecular determinants of VSOR, including the precise role of LRRC8 proteins.

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Human ClC-3 Is Not the Swelling-activated Chloride Channel Involved in Cell Volume Regulation

Cited by 90 publications

References 37 publications

ClC-3 Is a Fundamental Molecular Component of Volume-sensitive Outwardly Rectifying Cl− Channels and Volume Regulation in HeLa Cells and Xenopus laevis Oocytes

ClC-3 Is a Fundamental Molecular Component of Volume-sensitive Outwardly Rectifying Cl− Channels and Volume Regulation in HeLa Cells and Xenopus laevis Oocytes

Extracellular acidification elicits a chloride current that shares characteristics with I_Cl(swell)

Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)

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