The signal transduction system of the leukotriene D4 receptor

doi:10.1016/0165-6147(89)90206-X

Trends in Pharmacological Sciences

Volume 10, Issue 3, March 1989, Pages 103-107

https://doi.org/10.1016/0165-6147(89)90206-X Get rights and content

Abstract

During the past several years, substantial progress in understanding the receptors and signal transduction processes for peptidyl leukotrienes has been reported. Receptors have been identified and characterized, the major steps in the signal transduction pathway have been described, and the genetic and epigenetic regulatory processes have been characterized. Very recent studies have defined the mechanisms by which LTE₄ acts as a partial agonist at the LTD₄ receptor. The cloning of the genes for the proteins involved in the major steps of the signalling process has also been initiated. Stanley Crooke and co-authors summarize this recent progress and present their current notions about the LTD₄ receptor signalling process.

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Cited by (85)

Modulation of leukotriene D<inf>4</inf> attenuates the development of seizures in mice
2011, Prostaglandins Leukotrienes and Essential Fatty Acids
Citation Excerpt :
However, the detailed dissection of the complete transduction system following the leukotriene D4 receptor activation that is leading to the epilepsy still requires further experimental assessment. Studies [56–59] have demonstrated that LTD4 activation of the cysteinyl leukotriene-1 (CysLT1) receptor leads to G-protein activation and the release of several second intracellular messengers, namely, diacylglycerol, inositol phosphates and Ca2+, events which are then followed by activation of protein kinase C (PKC) and accompanied by the mobilization of Ca2+ derived from both intracellular and extracellular stores. Further, Clark et al. [60] have demonstrated that LTD4 activation of CysLT1 receptors also cause the release of arachidonic acid via stimulation of phospholipase A2, which was associated with an enhanced transcription of phospholipase A2 activating protein.
The present study has been designed to pharmacologically investigate the effect of Montelukast sodium, a leukotriene D₄ receptor antagonist, and 1,2,3,4, tetrahydroisoquinoline, a leukotriene D₄ synthetic pathway inhibitor, on the pathophysiological progression of seizures using mouse models of kindled epilepsy and status epilepticus induced spontaneous recurrent seizures. Pentylenetetrazole (40 mg kg⁻¹) (PTZ) administration every second day for a period of 15 d was used to elicit chemically induced kindled seizure activity in mice. In a separate set of groups, fifty consecutive electroshocks were delivered to mice using corneal electrodes with continuously increasing intensity with an inter-shock interval of 40 s. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score (KSSS). Pilocarpine (100 mg kg⁻¹) was injected every twenty minutes until the onset of status epilepticus. A spontaneous recurrent seizure severity score (SRSSS) was recorded as a measure of quantitative assessment of the progressive development of spontaneous recurrent seizures induced after pilocarpine status epilepticus. Sub-acute PTZ administration and electroshock induced the development of severe form of kindled seizures in mice. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score. Further, pharmacological status epilepticus elicited a progressive evolution of spontaneous recurrent seizures in the animals. However, Montelukast sodium, a leukotriene D₄ receptor antagonist, as well as 1,2,3,4, tetrahydroisoquinoline, a leukotriene D₄ synthetic pathway inhibitor, markedly and dose dependently suppressed the development of kindled seizures as well as pilocarpine induced spontaneous recurrent seizures. Therefore, leukotriene D₄ may be implicated in the pathogenesis of seizures.
CysLT<inf>1</inf> signal transduction in differentiated U937 cells involves the activation of the small GTP-binding protein Ras
2004, Biochemical Pharmacology
Citation Excerpt :
While in recombinant cell systems CysLT1 was shown to be preferentially coupled to Gq/11[5,6], soon it became clear that heterogeneity of pathways has to be expected among endogenous tissues and cells. Indeed, naturally expressed CysLT1 receptor has been reported to activate both pertussis toxin (PTx)-sensitive and -insensitive G-proteins [12,13]. This by no means a surprise, as it has been recognized that the use of recombinant systems, especially when dealing with signal transduction pathway(s) of G protein-coupled receptors (GPCRs) [14], might produce results whose general validity is sometimes questionable and cannot be easily extrapolated to endogenous cells.
We investigated the signal transduction pathway(s) of leukotriene D₄ (LTD₄) in the human promonocytic U937 cells, a cell line known to constitutively express CysLT₁ receptors. Herein, we demonstrate that LTD₄ specifically acts on a CysLT₁ receptor to dose-dependently increase (three to five-fold over basal) RasGTP through a G_i/o protein. In fact, while cytosolic Ca²⁺ ([Ca²⁺]_i) increase was only partially sensitive to pertussis toxin (PTx), Ras activation was almost completely inhibited by the same toxin. Furthermore, the phospholipase C (PLC) inhibitor U73122 completely inhibited both [Ca²⁺]_i and RasGTP increase, suggesting that in these cells PLC is the point of convergence for both PTx insensitive and sensitive pathways leading to [Ca²⁺]_i release and Ras activation. Indeed, chelating intracellular Ca²⁺ strongly (>70%) prevented LTD₄-induced Ras activation, indicating that this ion plays an essential role for CysLT₁-induced downstream signaling in differentiated U937 (dU937) cells. In addition, while Src did not appear to be substantially involved in CysLT₁-induced signaling, genistein was able to partially inhibit LTD₄-induced [Ca²⁺]_i transient (∼34%) and almost completely prevented Ras activation (>90%), suggesting a potential role for other Ca²⁺-dependent tyrosine kinases in LTD₄-induced signaling. Finally, agonist-induced CysLT₁ stimulation was followed by a specific extracellular regulated kinase (ERK) 1/2 phosphorylation, an event with a pharmacological profile similar to that of Ras activation, partially (∼40%) sensitive to Clostridium sordellii lethal toxin and totally blocked by PTx. In conclusion, LTD₄-induced CysLT₁ receptor activation in dU937 cells leads to Ras activation and ERK phosphorylation mostly through a PTx-sensitive G_i/o protein, PLC, and Ca²⁺-dependent tyrosine kinase(s).
Bronchodilator effect of zafirlukast in subjects with chronic obstructive pulmonary disease
2003, Pulmonary Pharmacology and Therapeutics
Cysteinyl leukotrienes (LT) are involved in airway inflammation and mucus hypersecretion, characteristically present in asthma and chronic obstructive pulmonary disease (COPD). Zafirlukast is an LT receptor antagonist that improves airway function within 1–3 h after oral administration in subjects with chronic persistent asthma. Through a randomised, double-blind, crossover and placebo-controlled study, we assessed the short-term effects of zafirlukast in patients with severe COPD. We enrolled 23 subjects (seven women) aged 59.4 (1.67) yr [mean (SEM)] with a smoking history of 60.7 (5.2) pack-yr. At screening day the mean FEV₁was 0.876 (0.72) l; FEV₁ % predicted=35 (3)% and 107 (14) ml increment post-salbutamol. They came two different days, apart from each other at least 72 h. After baseline spirometry, a single oral dose of 40 mg zafirlukast or the corresponding placebo was administered. FVC and FEV₁ was measured every 30 min until 2 hrs. On zafirlukast day, the mean FEV₁ at 90 min [0.813 (0.64) l] and the mean FVC at 90 min [1.76 (0.1) l] were significantly higher than the respective means at placebo day (mean FEV₁=0.747 (0.55) l; mean FVC=1.63 (0.1) l; p<0.05 Tukey Kramer multiple comparisons test). The maximum mean increase in FEV₁ was 75 (19) ml. A positive correlation was found between absolute response to salbutamol in FEV₁ and the response to zafirlukast (r=0.41; p<0.04). In conclusion, these findings suggest that zafirlukast has a bronchodilator or antibronchoconstrictor effect in COPD patients with severe airflow limitation.
Involvement of prenylated proteins in calcium signaling induced by LTD<inf>4</inf> in differentiated U937 cells
2003, Prostaglandins and Other Lipid Mediators
We investigated signal transduction pathways for LTD₄ in the human promonocytic cell line U937 known, upon differentiation, to express CysLT₁ receptors. We confirmed the presence of high-affinity binding sites for $^{3} H$ -LTD₄, which, in functional studies, displayed the features of CysLT₁ receptor. In fact, three potent and selective CysLT₁ receptor antagonists were able to completely inhibit LTD₄-induced response. In turn, cytosolic Ca²⁺ ([Ca²⁺]_i) increase (EC₅₀=3.4 nM±27% CV) was only partially sensitive to pertussis toxin (PTx) as well as to the prenylation inhibitor fluvastatin and to the specific geranylgeranylation and farnesylation inhibitors BAL 9504 and FPT II. Finally, Clostridium sordellii lethal toxin, inhibitor of the Ras family of GTPases, and FTS, a potent methyltransferase inhibitor, were both able to partially inhibit LTD₄-induced [Ca²⁺]_i increase, suggesting a role for a Ras family member in [Ca²⁺]_i regulation. In conclusion, in dU937 LTD₄ signal transduction involves: (a) at least two pathways, one sensitive and one insensitive to PTx; (b) isoprenylated proteins, such as βγ subunits and, possibly, a small G protein of the Ras family.
Cysteinyl leukotriene receptors
2002, Prostaglandins and Other Lipid Mediators
The cysteinyl leukotrienes, leukotriene C₄ (LTC₄), leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄), activate contractile and inflammatory processes via specific interaction with putative seven transmembrane-spanning receptors that couple to G proteins and subsequent intracellular signaling pathways. Pharmacological characterizations identified at least two subtypes of cysteinyl leukotriene (CysLT) receptor based on agonist and antagonist potency for biological responses. The rank potency of agonist activation for the CysLT₁ receptor is LTD₄>LTC₄>LTE₄ and for the CysLT₂ receptor is LTC₄=LTD₄>LTE₄. CysLT₁ selective receptor antagonists are efficacious in the treatment of asthma. No selective CysLT₂ receptor antagonists have been described. Molecular identification of the human and mouse CysLT₁ and CysLT₂ receptors has confirmed their structure as putative seven transmembrane domain G protein-coupled receptors and largely confirmed the previous pharmacological characterizations. The CysLT₁ receptor is most highly expressed in spleen, peripheral blood leukocytes including eosinophils, and lung smooth muscle cells and interstitial lung macrophages. The CysLT₂ receptor is most highly expressed in the heart, adrenal medulla, placenta and peripheral blood leukocytes. The molecular identification of the mouse CysLT₁ and CysLT₂ receptors show similar but not identical profiles to the orthologous human receptors.
Human mast cells express two leukotriene C<inf>4</inf> synthase isoenzymes and the CysLT<inf>1</inf> receptor
2002, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Cysteinyl-leukotrienes (cys-LTs) are potent smooth muscle contracting agents, especially in the respiratory tract and microcirculation, and play a key role in inflammatory and allergic diseases. The final step in the biosynthesis of LTC₄, the parent compound of cys-LTs, is catalyzed by a specific GSH transferase termed LTC₄ synthase, which is typically expressed in certain bone marrow-derived cells such as eosinophils and mast cells.
Here we report that the human mast cell line HMC-1 as well as human mast cells derived from cord blood (CBMC) express a second enzyme capable of synthesizing leukotriene C₄, i.e., microsomal GSH transferase type 2. Furthermore, these cells abundantly express CysLT₁ receptors that are mostly located at the surface of both types of mast cells, as judged by immunohistochemistry. In addition, stimulation of CBMC with LTC₄ and LTD₄ elicits an immediate and dose-dependent (10⁻⁷–10⁻¹¹ M) mobilization of intracellular Ca²⁺, which can be blocked with specific CysLT₁ receptor antagonists. Taken together, our data suggest that human mast cells are equipped with two enzymes that can catalyze the committed step in the biosynthesis of cys-LTs. Moreover, the expression of the cognate receptor CysLT₁ suggests that these lipid mediators may be involved in autocrine signaling pathways regulating mast cell functions.

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Tips reviewsThe signal transduction system of the leukotriene D4 receptor

Abstract

J. Biol. Chem.

Eur. J. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Mol. Pharmacol.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Mol. Pharmacol.

Ann. NY Acad. Sci.

J. Exp. Med.

J. Pharmacol. Exp. Ther.

Tips reviews
The signal transduction system of the leukotriene D₄ receptor