Cysteinyl leukotriene (CysLT) receptor antagonists, specifically CysLT1 antagonists, have become a mainstay in the treatment of allergies and asthma. The role of CysLT2 in asthma remains to be determined; however, a polymorphism in CysLT2 resulting in the M201V substitution has been found to be associated with asthma in several population studies. Brochu-Bourque et al. investigated the effect of the M201V substitution on the affinity of CysLT2 for leukotriene (LT) C4 and LTD4 and the subsequent activation of signaling. The M201V substitution dramatically reduced CysLT2 responses to LTD4 but had lesser effect on LTC4 responses. The polymorphism also affected the signaling efficiency of CysLT2, impairing inositol phosphate generation, activation of the interleukin-8 promoter, and the phosphorylation of nuclear factor-κB (NFκB) p65, extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK). LTD4-stimulated cells did not phosphorylate NFκB p65 or JNK, whereas at higher concentrations, activation of p38 and ERK were maintained. The differential effects of the M201V substitution on signaling raise several questions regarding the potential for involvement of different G proteins or effects on cellular trafficking. The impact of the M201V mutation on other elements of the pathophysiology of asthma remains to be elucidated.
See article at J Pharmacol Exp Ther 2011, 336:431–439.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics