The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor

Cysteinyl leukotrienes (CysLTs), slow-reacting substances of anaphylaxis, a re Lipid mediators known to possess potent proinflammatory action. Pharmaco logical studies using CysLTs indicate that at least two classes of G protei n-coupled receptors (GPCRs), named CysLT(1) and CysLT(2), exist; the former is sensitive and the latter is resistant to the CysLT(1) antagonists curre ntly used to treat asthma. Although the CysLT(1) receptor gene has been rec ently cloned, the molecular identity of the CysLT(2) receptor has remained elusive. Here we show that the pharmacological profile of an orphan GPCR (P SEC0146) is consistent with that of the CysLT(2) receptor. In human embryon ic kidney 293 cells that express the PSEC0146 cDNA leukotriene C-4 (LTC4) a nd leukotriene D-4 (LTD4) induce equal increases in intracellular calcium m obilization; these increases are not affected by CysLT(1) antagonists. Addi tionally, [H-3]LTC4 specifically binds to membranes from COS-1 cells transi ently transfected with PSEC0146. Large amounts of the PSEC0146 mRNA are fou nd in human heart, placenta, spleen, and peripheral blood leukocytes but no t in the lung and the trachea. Pharmacological feature and expression studi es will eventually lead to a better understanding of the classification of CysLT receptors, possibly leading to a reconsideration of the pathological and physiological role of CysLTs. (C) 2000 Academic Press.