Involvement of prenylated proteins in calcium signaling induced by LTD4 in differentiated U937 cells

We investigated signal transduction pathways for LTD(4) in the human promonocytic cell line U937 known, upon differentiation, to express CysLT, receptors. We confirmed the presence of high-affinity binding sites for (3)H-LTD(4), which, in functional studies, displayed the features of CysLT(1) receptor. In fact, three potent and selective CysLT(1) receptor antagonists were able to completely inhibit LTD(4)-induced response. In turn, cytosolic Ca(2+) ([Ca(2+)](i) increase (EC(50) = 3.4 nM +/- E 27% CV) was only partially sensitive to pertussis toxin (PTx) as well as to the prenylation inhibitor fluvastatin and to the specific geranylgeranylation and farnesylation inhibitors BAL 9504 and FPT II. Finally, Clostridium sordellii lethal toxin, inhibitor of the Ras family of GTPases, and FTS, a potent methyltransferase inhibitor, were both able to partially inhibit LTD4-induced [Ca(2+)](i) increase, suggesting a role for a Ras family member in [Ca(2+)](i) regulation. In conclusion, in dU937 LTD(4) signal transduction involves: (a) at least two pathways, one sensitive and one insensitive to PTx; (b) isoprenylated proteins, such as betagamma subunits and, possibly, a small G protein of the Ras family. (C) 2003 Elsevier Science Inc. All rights reserved.