CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors.
Montelukast and pranlukast are orally active leukotriene receptor antagonists selective for the CysLT1 receptor. Conversely, the hP2Y(1,2,4,6,11,12,13,14) 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 microM, respectively, and inhibited the effects of UDP with IC50 values of 4.5 and 1.6 microM, 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 P2Y(1,2,4,6) 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 microM. In control astrocytoma cells expressing an endogenous M3 muscarinic receptor, 10 microM 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.
Mamedova
Liaman
L
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Capra
Valérie
V
Accomazzo
Maria Rosa
MR
Gao
Zhan-Guo
ZG
Ferrario
Silvia
S
Fumagalli
Marta
M
Abbracchio
Maria P
MP
Rovati
G Enrico
GE
Jacobson
Kenneth A
KA
D000085:Acetates / Q000494:pharmacology; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003521:Cyclopropanes; D017931:DNA Primers; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene; D018048:Receptors, Purinergic P2 / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013440:Sulfides; D020298:U937 Cells; D014544:Uridine Triphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000085:Acetates; D002867:Chromones; D003521:Cyclopropanes; D017931:DNA Primers; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D018048:Receptors, Purinergic P2; D013440:Sulfides; C083169:leukotriene D4 receptor; C093875:montelukast; D002118:Calcium; C047681:pranlukast; D014544:Uridine Triphosphate