Cellular signalling of cysteinyl leukotriene type 1 receptor variants CysLT1 -G300S and CysLT1 -I206S

Abstract Cysteinyl-leukotrienes are pro-inflammatory lipid mediators, involved in allergic asthma, that bind the G-protein-coupled receptors CysLT1 , CysLT2 and GPR99. A polymorphism in one of these receptors, CysLT1 -G300S was strongly associated with atopy, whereas the CysLT1 -I206S polymorphism was not. In the present work, our aim was to characterize these two variants by studying their cellular signalling. Cell surface expression of mutant receptors in transfected HEK-293 cells was comparable to that of the wild-type receptor. Compared to CysLT1 -WT, production of inositol phosphates as well as IL-8 and IL-13 promoter transactivation in response to either LTD4 or LTC4 was significantly increased in CysLT1 -G300S-transfected cells. Moreover, LTD4 -induced phosphorylation of the signalling effector Erk, but not p38, p65 or c-Jun was higher in CysLT1 -G300S-transfected cells. On the other hand, the variant CysLT1 -I206S did not show a significant difference in its signal transduction compared to the wild-type receptor. Taken together, our results indicate that the variant CysLT1 -G300S can induce a greater signal than the CysLT1 -WT receptor, a feature that may be relevant to its association with atopy.