Identification of the anion exchange protein of ehrlich cells: A kinetic analysis of the inhibitory effects of 4,4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS) and labeling of membrane proteins with3H-DIDS

Jessen, Flemming; Sjøholm, Carsten; Hoffmann, Else K.

doi:10.1007/bf01869388

Cited by 63 publications

(39 citation statements)

References 35 publications

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“…We hypothesize that DIDS suppresses virus release by inhibiting the 2B protein-mediated chloridedependent current. However, as a classic anion exchanger blocker, DIDS also has effects on the cells themselves [15]. Nevertheless, in our study, DIDS had no significant effect on either cell growth or morphology at relatively low concentrations (≤ 500 µM), suggesting that the inhibition of DIDS on EV71 production can be primarily attributed to its effects on the 2B-mediated current.…”

contrasting

confidence: 63%

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

Xie

Wang

et al. 2011

Cell Res

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Enterovirus 71 (EV71), which belongs to the genus Enterovirus of the family Picornaviridae, is one of the major pathogens that cause hand, foot and mouth disease, primarily in infants and young children. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in many countries and regions, including Japan, China and Taiwan [1]. However, there is still no effective antiviral treatment against severe EV71 infections, and no vaccine is available.During their life cycle, viruses can induce many changes in their host cells including increased plasma membrane permeability [2]. Although its detailed mechanism remains largely unknown, this effect on the plasma membrane could be due to the expression of many virusencoded proteins [3][4][5]. The expression of protein 2B from polioviruses and coxsackieviruses can increase the permeability of the cell membrane to the translational inhibitor hygromycin B [6,7]. A recent study that focused on protein 2B from coxsackievirus B3 (CVB3) showed that 2B can facilitate virus release by increasing the concentration of free cytosolic Ca 2+ [8]. However, little is known about 2B proteins from other enteroviruses, and the detailed mechanisms of how 2B changes cellular ion homeostasis and, thus, promotes virion release remain unclear.Because the 2B protein of CVB3 can form homodimers and homotetramers that are located primarily in the cell membrane system, including the Golgi complex [9, 10], we asked whether the 2B proteins of EV71 might share similar characteristics. To address this question, the sequences of the 2B genes from these two viruses were compared. These sequences have relatively high similarity, especially within their two transmembrane domains (TM1 and TM2), structures that are essential for the function of viroporins (Supplementary information, Figure S1A). Next, we examined the subcellular localization of the EV71 2B protein in human rhabdomyosarcoma (RD) cells and found that it colocalized with the Golgi complex (Supplementary information, Figure S1B).

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contrasting

confidence: 63%

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

Xie

Wang

et al. 2011

Cell Res

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“…4,4′-Diisothiocyano-2,2′-stilbenedisulphonic acid (DIDS) (compound 20; FIG. 4)and structurally related stilbenes act as inhibitors of anion exchangers, but they also indiscriminately inhibit other HCO 3 -transporters 75 . These compounds initially block the anion exchangers reversibly and later block them irreversibly 75 .…”

Section: Compound Genericmentioning

confidence: 99%

“…4)and structurally related stilbenes act as inhibitors of anion exchangers, but they also indiscriminately inhibit other HCO 3 -transporters 75 . These compounds initially block the anion exchangers reversibly and later block them irreversibly 75 . DIDS has antitumour activity and it induces apoptosis in HA22T hepatocellular carcinoma cells overexpressing AE2…”

Section: Compound Genericmentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,396

1,269

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The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

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“…Stilbene derivatives, such as 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid (DIDS) and 4-acetamido-4Ј-isothiocyanatostilbene-2,2Ј-disulfonic acid (SITS), are known to inhibit Cl Ϫ channels and transporters (Jessen et al, 1986;Dietrich and Lindau, 1994;Lai et al, 1996;Lane et al, 1999;Matulef and Maduke, 2005). In addition, DIDS also was reported to be able to inhibit TRP canonical 4 (Walker et al, 2002) and TRP melastatin 4 (Morita et al, 2007) currents.…”

Section: Introductionmentioning

confidence: 99%

Agonist-Dependent Potentiation of Vanilloid Receptor Transient Receptor Potential Vanilloid Type 1 Function by Stilbene Derivatives

Zhang

Du²,

Zhang³

et al. 2012

Molecular Pharmacology

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Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel activated by capsaicin, low pH, and noxious heat and plays a key role in nociception. Understanding mechanisms for functional modulation of TRPV1 has important implications. One characteristic of TRPV1 is that channel activity induced by either capsaicin or other activators can be sensitized or modulated by factors involving different cell signaling mechanisms. In this study, we describe a novel mechanism for the modulation of TRPV1 function: TRPV1 function is modulated by 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid (DIDS) and its analogs. We found that, in rat dorsal root ganglion neurons, although DIDS did not induce the activation of TRPV1 per se but drastically increased the TRPV1 currents induced by either capsaicin or low pH. DIDS also blocked the tachyphylaxis of the low pH-induced TRPV1 currents. 4-Acetamido-4Ј-isothiocyanatostilbene-2,2Ј-disulfonic acid (SITS), a DIDS analog, failed to enhance the capsaicin-evoked TRPV1 current but increased the low pH-evoked TRPV1 currents, with an effect comparable with that of DIDS. SITS also blocked the low pH-induced tachyphylaxis. DIDS also potentiated the currents of TRPV1 channels expressed in human embryonic kidney 293 cells, with an effect of left-shifting the concentrationresponse curve of the capsaicin-induced TRPV1 currents. This study demonstrates that DIDS and SITS, traditionally used chloride channel blockers, can modify TRPV1 channel function in an agonist-dependent manner. The results provide new input for understanding TRPV1 modulation and developing new modulators of TRPV1 function.

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Identification of the anion exchange protein of ehrlich cells: A kinetic analysis of the inhibitory effects of 4,4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS) and labeling of membrane proteins with3H-DIDS

Cited by 63 publications

References 35 publications

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

Interfering with pH regulation in tumours as a therapeutic strategy

Agonist-Dependent Potentiation of Vanilloid Receptor Transient Receptor Potential Vanilloid Type 1 Function by Stilbene Derivatives

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