Cysteinyl Leukotriene Receptor 1 is Also a Pyrimidinergic Receptor and is Expressed by Human Mast Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-07, Vol.98 (14), p.7964-7969
• Main Authors: Mellor, Elizabeth A., Maekawa, Akiko, Austen, K. Frank, Boyce, Joshua A.
• Format: Article
• Language: English
• Subjects: Agonists; Amino Acid Sequence; Animals; Asthma; Biological Sciences; Calcium; Cells; CHO Cells; Cricetinae; cysteinyl leukotriene receptor 1; Genes; Humans; Immunology; Inflammation - immunology; Leukotriene Antagonists - pharmacology; Leukotrienes; Lipids; Mast cells; Mast Cells - immunology; Membrane Proteins; Molecular Sequence Data; Peptides; Propionates - pharmacology; pyrimidinergic receptors; Pyrimidines - immunology; Quinolines - pharmacology; Receptors; Receptors, Leukotriene - immunology; RNA; RNA, Messenger - analysis; Sequence Alignment; Stem cells; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.141221498

The cysteinyl leukotrienes (cys-LTs)$LTC_4, \> LTD_4$, and LTE4are a class of peptide-conjugated lipids formed from arachidonic acid and released during activation of mast cells (MCs). We now report that human cord-blood-derived MCs (hMCs) express the CysLT1 receptor, which responds not only to inflammation-derived cys-LTs, but also to a pyrimidinergic ligand, UDP. hMCs express both CysLT1 protein and transcript, and respond to$LTC_4, \> LTD_4$, and UDP with concentration-dependent calcium fluxes, each of which is blocked by a competitive CysLT1 receptor antagonist, MK571. Stably transfected Chinese hamster ovary cells expressing the CysLT1 receptor also exhibit MK571-sensitive calcium flux to all three agonists. Both hMCs and CysLT1 transfectants stimulated with UDP are desensitized to LTC4, but only partially to LTD4. Priming of hMCs with IL-4 for 5 days enhances their sensitivity to each agonist, but preferentially lowers their threshold for activation by LTC4and UDP (≈3 log10-fold shifts in dose-response for each agonist) over LTD4(1.3 log10-fold shift), without altering CysLT1 receptor mRNA or surface protein expression, implying the likely induction of a second receptor with CysLT1-like dual ligand specificity. hMCs thus express the CysLT1 receptor, and possibly a closely related IL-4-inducible receptor, which mediate dual activation responses to cys-LTs and UDP, providing an apparent intersection linking the inflammatory and neurogenic elements of bronchial asthma.