Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors
Sagan, S.; Chassaing, G.; Pradier, L.; Lavielle, S.
Journal of Pharmacology and Experimental Therapeutics 276(3): 1039-1048
1996
ISSN/ISBN: 0022-3565 PMID: 8786533 Document Number: 461144
The human NK-1 receptor transfected in Chinese hamster ovary (CHO) cells was studied with use of different tachykinin analogs: Substance P, (Pro-9)SP, (Sar-9, Met(O-2)-11)SP, (Gly-9-PSI(CH-2CH-2) Leu-10)SP, Ac-Arg-septide, septide, (Gly-9-PSI(CH-2CH-2) Gly-10)SP, NKA, (pGlu-6)SP(6-11) and (Lys-5)NKA(4-10). Binding experiments with (3H)(Pro-9)SP discriminated two classes of peptides with either high affinity (K-i in the nanomolar range) for the human NK-1 receptor or with low affinity (K i in the micromolar range); this second group of peptides included NKA and (pGlu-6)SP(6-11). In spite of these differences, both peptide families evoked potent stimulation of phosphatidylinositol hydrolysis (EC-50 in the nanomolar range). In contrast, only NK-1 agonists, with high affinity, stimulated with great potency cyclic AMP formation (EC-50 from 8 to 50 nM), whereas the second family of peptides were only weak agonists (EC-50 in the micromolar range). RP 67580, CP 96345 and GR 94800, a NK-2 antagonist, were either competitive or uncompetitive inhibitors of inositol phosphates or cyclic AMP formations induced by (Pro-9)SP, septide or NKA, independently of the agonist or the response studied. Thus, NKA, the presumed NK-2 endogenous peptide that may be co-released with SP, and the enzymatically produced C-terminal fragment of SP, (pGlu-6)SP(6-11), may trigger specific pharmacological responses via the NK-1 receptor, at nanomolar concentrations, and thus regulate the action of SP at the NK-1 receptor.