Double Mutation at the Putative Protein Kinase C Phosphorylation Sites Thr151Plus Thr323in the Mouse LeukotrieneD4Receptor Eliminates Homologous Desensitization

Jørgensen, Sune T.; Eriksen, Heidi N.; Dausell, Janni; Jespersen, Thomas; Lambert, Ian Henry; Hoffmann, Else K.

doi:10.1159/000343374

Cited by 3 publications

(3 citation statements)

References 54 publications

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“…It has been also demonstrated in several cell lines that inhibition of the 5-LO blocks volume restoration following osmotic cell swelling (30, 43) and the concomitant release of taurine (34,36). We have demonstrated that, in Ehrlich ascites tumor cells, leukotriene D 4 plays a key role in the activation of volume-sensitive transporters for K ϩ (15) and amino acids (31) and hence restoration of the cell volume following osmotic cell swelling (16,22,39). The 5-LO is a non-heme iron containing enzyme that is inactive when the iron is in the ferro state (Fe 2ϩ ) and active when the iron is in its oxidized ferri state (Fe 3ϩ ).…”

mentioning

confidence: 83%

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Holm

Grygorczyk

Lambert

2013

American Journal of Physiology-Cell Physiology

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Holm JB, Grygorczyk R, Lambert IH. Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase. Am J Physiol Cell Physiol 305: C48-C60, 2013. First published March 13, 2013; doi:10.1152/ajpcell.00412.2012.-Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration, and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT1) with the antiasthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium-sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H 2O2. Ca 2ϩ mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca 2ϩ (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H2O2, ATP, and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT1 as essential elements in the swelling-induced activation of VSOAC with ROS and Ca 2ϩ as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase-3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT1 but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia. 5-lipoxygenase; lung adenocarcinoma; cysteinyl leukotriene 1 receptor; hypoxia; ischemia; cell volume regulation; reactive oxygen species; taurine homeostasis WITHIN RECENT YEARS it has become clear that cell volume regulation under isotonic conditions and cell volume restoration following osmotic perturbations are important for regulation of the intracellular milieu and cellular functions, such as cell metabolism, cell migration, and control of cell death (see refs. 16, 39). Cells maintain a steady cell volume by regulating the intracellular concentrations of ions (mainly Na ϩ , K ϩ , and Cl Ϫ ) and organic osmolytes (16,39). A consequence of hypotonic cell swelling is net loss of KCl and amino acids including the ␤-amino ethane sulfonic acid, taurine.Taurine: a multifunctional amino acid. Taurine is the most abundant free amino acid of the human body and has been estimated to account for up to 38% of the total free amino acid pool in rat heart ce...

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confidence: 83%

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Holm

Grygorczyk

Lambert

2013

American Journal of Physiology-Cell Physiology

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“…Furthermore, PKC‐mediated phosphorylation/desensitization of the mCysLT1 receptor have recently been assigned a role in abrogation of the RVD response (Jorgensen et al . ).…”

Section: Taurine Transportersmentioning

confidence: 97%

Physiological role of taurine – from organism to organelle

et al. 2014

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Taurine is often referred to as a semi-essential amino acid as newborn mammals have a limited ability to synthesize taurine and have to rely on dietary supply. Taurine is not thought to be incorporated into proteins as no aminoacyl tRNA synthetase has yet been identified and is not oxidized in mammalian cells. However, taurine contributes significantly to the cellular pool of organic osmolytes and has accordingly been acknowledged for its role in cell volume restoration following osmotic perturbation. This review describes taurine homeostasis in cells and organelles with emphasis on taurine biophysics/membrane dynamics, regulation of transport proteins involved in active taurine uptake and passive taurine release as well as physiological processes, for example, development, lung function, mitochondrial function, antioxidative defence and apoptosis which seem to be affected by a shift in the expression of the taurine transporters and/or the cellular taurine content.

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“…The phosphatase required for PTEN activation has not been identified, and it is also unknown whether PTEN activity is affected by osmotic cell swelling. Abrogation of the volume-regulatory process in EATC involves PKC-mediated phosphorylation and desensitization of the CysLT1 receptor (18). VSOAC has not been cloned although date indicates that it is different from volume-sensitive Cl Ϫ channels (27,29) and Ca 2ϩ -sensitive Cl Ϫ channels (19).…”

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confidence: 99%

mTOR ensures increased release and reduced uptake of the organic osmolyte taurine under hypoosmotic conditions in mouse fibroblasts

Lambert

Jensen

Pedersen

2014

American Journal of Physiology-Cell Physiology

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Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that modulates translation in response to growth factors and alterations in nutrient availability following hypoxia and DNA damage. Here we demonstrate that mTOR activity in Ehrlich Lettré ascites (ELA) cells is transiently increased within minutes following osmotic cell swelling and that inhibition of phosphatidylinositol-3-phosphatase (PTEN) counteracts the upstream phosphatidylinositol kinase and potentiates mTOR activity. PTEN inhibition concomitantly potentiates swelling-induced taurine release via the volume-sensitive transporter for organic osmolytes and anion channels (VSOAC) and enhances swelling-induced inhibition of taurine uptake via the taurine-specific transporter (TauT). Chronic osmotic stress, i.e., exposure to hypotonic or hypertonic media for 24 h, reduces and increases mTOR activity in ELA cells, respectively. Using rapamycin, we demonstrate that mTOR inhibition is accompanied by reduction in TauT activity and increase in VSOAC activity in cells expressing high (NIH3T3 fibroblasts) or low (ELA) amounts of mTOR protein. The effect of mTOR inhibition on TauT activity reflects reduced TauT mRNA, TauT protein abundance, and an overall reduction in protein synthesis, whereas the effect on VSOAC is mimicked by catalase inhibition and correlates with reduced catalase mRNA abundance. Hence, mTOR activity favors loss of taurine following hypoosmotic cell swelling, i.e., release via VSOAC and uptake via TauT during acute hypotonic exposure is potentiated and reduced, respectively, by phosphorylation involving mTOR and/or the kinases upstream to mTOR. Decrease in TauT activity during chronic hypotonic exposure, on the other hand, involves reduction in expression/activity of TauT and enzymes in antioxidative defense.

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Double Mutation at the Putative Protein Kinase C Phosphorylation Sites Thr¹⁵¹Plus Thr³²³in the Mouse LeukotrieneD₄Receptor Eliminates Homologous Desensitization

Cited by 3 publications

References 54 publications

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Physiological role of taurine – from organism to organelle

mTOR ensures increased release and reduced uptake of the organic osmolyte taurine under hypoosmotic conditions in mouse fibroblasts

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