Montelukast and pranlukast are orally active leukotriene receptor antagonists selective for the CysLT1 receptor. Conversely, the hP2Y1,2,4,6,11,12,13,14 receptors represent a large family of GPCRs responding to either adenine or uracil nucleotides, or to sugar-nucleotides. Montelukast and pranlukast were found to inhibit nucleotide-induced calcium mobilization in a human monocyte-macrophage like cell line, DMSO-differentiated U937 (dU937). Montelukast and pranlukast inhibited the effects of UTP with IC50 values of 7.7 and 4.3 mM, respectively, and inhibited the effects of UDP with IC50 values of 4.5 and 1.6 mM, respectively, in an insurmountable manner. Furthermore, ligand binding studies using [3H]LTD4 excluded the possibility of orthosteric nucleotide binding to the CysLT1 receptor. dU937 cells were shown to express P2Y2, P2Y4, P2Y6, P2Y11, P2Y13 and P2Y14 receptors. Therefore, these antagonists were studied functionally in a heterologous expression system for the human P2Y receptors. In 1321N1 astrocytoma cells stably expressing human P2Y1,2,4,6 receptors, CysLT1 antagonists inhibited both the P2Y agonist-induced activation of phospholipase C and intracellular Ca2+ mobilization. IC50 values at P2Y1 and P2Y6 receptors were <1 mM. In control astrocytoma cells expressing an endogenous M3 muscarinic receptor, 10 mM montelukast had no effect on the carbachol-induced rise in intracellular Ca2+. These data demonstrated that CysLT1 receptor antagonists interact functionally with signaling pathways of P2Y receptors, and this should foster the study of possible implications for the clinical use of these compounds in asthma or in other inflammatory conditions.
|Titolo:||CysLT(1) leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors|
|Autori interni:||ROVATI, GIANENRICO (Penultimo)|
CAPRA, VALERIE CAROLINE (Secondo)
ACCOMAZZO, MARIA ROSA
ABBRACCHIO, MARIA PIA
|Parole Chiave:||Montelukast Pranlukast Purine receptors Nucleotides ATP UDP|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2005|
|Digital Object Identifier (DOI):||10.1016/j.bcp.2005.10.003|
|Appare nelle tipologie:||01 - Articolo su periodico|
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