Molecular identification of a volume-regulated chloride channel

Duan, Dayue Darrel; Winter, Cathy R.; Cowley, Suzanne; Hume, Joseph R.; Horowitz, Burton

doi:10.1038/37151

Cited by 422 publications

(455 citation statements)

References 27 publications

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“…This P-gpassociated volume-regulated chloride channel is functionally blocked by P-gp-specific mAbs (42,43) and MDR1 antisense oligonucleotides (44). A molecular candidate for the volume-regulated chloride channel, ClC-3, has recently been identified, and was shown to be inhibited by the chloride channel-specific inhibitor 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid and the P-gp inhibitor tamoxifen (45). Since T cell activation depends in part on efficient cell-cell interactions during Ag recognition and costimulation, P-gp, through its associated chloride channel activity (46), may function as a regulator of cellular volume changes and cell shape adaptations during these processes.…”

Section: Discussionmentioning

confidence: 99%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1–10 μM) and the MDR1 P-gp-specific mAb Hyb-241 (1–20 μg/ml), which detected surface P-gp on 21% of human CD3+ T cells and 84% of CD14+ APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40–90% (p < 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with >85% inhibition (p < 0.01) of IL-2, IFN-γ, and TNF-α production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1–10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4+ T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4+ T cellular IFN-γ secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4+ T cells and CD14+ APCs, and that P-gp blockade may attenuate both IFN-γ and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.

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Section: Discussionmentioning

confidence: 99%

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Frank

Denton

Alexander

et al. 2001

The Journal of Immunology

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“…1 The roles of VSOR in cell volume regulation, proliferation, migration and cell death are well established, but its molecular identity has not fully been clarified until recently. 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.…”

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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“…In this regard, it would npg not be hard to imagine that AQP3 might also form molecular complexes with other ion channels to mediate sperm RVD. Such candidate molecules may involve the volume sensitive chloride channel CLC-3 [30] , which has been observed in mammalian sperm and has been implicated in sperm volume regulation [31,32] .…”

Section: Efficient Sperm Volume Regulation Is a Prerequisite For Normmentioning

confidence: 99%

Aquaporins in sperm osmoadaptation: an emerging role for volume regulation

Chen

Duan

2011

Acta Pharmacol Sin

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Upon ejaculation, mammalian sperm experience a natural osmotic decrease during male to female reproductive tract transition. This hypo-osmotic exposure not only activates sperm motility, but also poses potential harm to sperm structure and function by inducing unwanted cell swelling. In this physiological context, regulatory volume decrease (RVD) is the major mechanism that protects cells from detrimental swelling, and is essential to sperm survival and normal function. Aquaporins are selective water channels that enable rapid water transport across cell membranes. Aquaporins have been implicated in sperm osmoregulation. Recent discoveries show that Aquaporin-3 (AQP3), a water channel protein, is localized in sperm tail membranes and that AQP3 mutant sperm show defects in volume regulation and excessive cell swelling upon physiological hypotonic stress in the female reproductive tract, thereby highlighting the importance of AQP3 in the postcopulatory sperm RVD process. In this paper, we discuss current knowledge, remaining questions and hypotheses about the function and mechanismic basis of aquaporins for volume regulation in sperm and other cell types. Efficient sperm volume regulation is a prerequisite for normal sperm functionIn most mammalian species studied, the journey of sperm from the male to the female reproductive tract experience a natural osmotic decrease [1] , an evolutionary vestige from freshwater fi sh species [2] . Before ejaculation, the mammalian sperm are quiescent in the relatively hypertonic male reproductive tract with no or very low motility. Upon copulation, the sperm enter into the relatively hypotonic female reproductive tract and quickly show motility activation [3,4] , indicating that osmotic changes are beneficial for initial sperm motility activation. However, postcopulatory hypotonic stress also has a negative effects as it induces osmotic cell swelling, which if uncontrolled, can be detrimental to sperm function and survival [5] . Mammalian sperm have evolved to effectively reduce the negative impact of hypotonic cell swelling by means of regulatory volume decrease (RVD), which was proposed to involve efficient volume regulation driven by active solute transport and rapid transmembrane water movement [6] .Functional importance of aquaporins in sperm volume regulation: emerging evidence from AQP3 knockout miceIn the early 1970s, it was demonstrated that the water permeability coefficient of bull spermatozoa was quite high, about four times greater than that of bovine erythrocytes and between ten and thirty times greater than that of artificial bimolecular lipid membranes [7] . According to these observations, the author made an insightful conclusion that the chief route for the passage of water through the sperm membrane must be via "pores" [7] . Similar high water permeability coefficients have been discovered in other mammalian species, including humans [8,9] .In the past two decades, the understanding of the movement of water through cell membranes has been greatly advanced by ...

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Molecular identification of a volume-regulated chloride channel

Cited by 422 publications

References 27 publications

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro

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

Aquaporins in sperm osmoadaptation: an emerging role for volume regulation

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