Nonetheless, 6-keto-PGF1?-G, the secure breakdown products of PGI2-G, was not detectable from the cells. Similarly, Rockwell et al. demonstrated that 2-AG, AEA, and noladin ether inhibit IL-2 secretion in activated Jurkat T cells and main splenocytes.111 The effect was blocked by selective inhibitors of COX-2 along with a PPAR-? antagonist. The results suggest the result was attributable to a COX- 2-dependent metabolite of 2-AG; on the other hand, the finding the same effect might be observed upon addition of AA suggests that a absolutely free acid PG may be the lively agent.87 3.2.2. Action at Novel Receptors. Several reports recommend that PG-Gs and/or PG-EAs have biological routines distinct from these of their free of charge acid counterparts and may act at novel receptors.
Quite possibly the most in depth scientific studies of this nature have centered on selleck chemical raf kinase inhibitor the biological activity of PGF2?-EA given that, as noted over, an analogue of this compound is used clinically inside the therapy of glaucoma. Within the eye, PGF2?-EA and its clinical counterpart bimatoprost have effects much like these of PGF2? on ocular stress. Nonetheless, intensive pharmacologic information indicate that these compounds never act with the FP receptor.75,107 The discovery of antagonists that block the action of PGF2?-EA and bimatoprost but not PGF2? in the eye additional supports the conclusion that one can find distinct online websites of action for these two compounds.112,113 Efforts to characterize a particular PGF2?-EA receptor led Liang et al.
to identify six splice variants with the FP receptor in human ocular tissues.114 They showed that HEK293/EBNA cells coexpressing the wild-type FP as well as altFP4 splice variant responded to both PGF2? and PGF2?-EA binding with distinct patterns of Ca2+ mobilization. The response to PGF2?-EA vx 770 but not PGF2? was blocked by antagonists to bimatoprost. Only PGF2? mobilized Ca2+ in HEK298/EBNA cells expressing the wild-type FP receptor alone. The FP receptor exists like a homodimer. Liang et al. showed that cells expressing both wild-type FP and altFP4 kind heterodimers of your two receptor gene goods. They propose that it can be this heterodimeric receptor that responds to PGF2?-EA and bimatoprost. It will likely be fascinating to view if this paradigm applies to other biologically active ester and amide derivatives of prostanoids.
Although not as sophisticated since the pharmacology of PGF2?-EA, some progress has been made on characterizing distinct biological actions of PG-Gs. Nirodi et al. showed that PGE2-G, but not PGD2-G, or PGF2?-G induced Ca2+ mobilization in RAW264.7 cells.106 The EC50 for this response was one pM, as in comparison to 15 nM for PGF2?.