Evidence that the proposed novel human "neurokinin-4" receptor is pharmacologically similar to the human neurokinin-3 receptor but is not of human origin

There have been proposals that the tachykinin receptor classification shoul d be extended to include a novel receptor, the "neurokinin-4" receptor (NK- 4R), which has a close homology with the human NK-3 receptor (hNK-3R). We c ompared the pharmacological and molecular biological characteristics of the hNK-3R and NK-4R. Binding experiments, with I-125-[MePhe(7)]-NKB binding t o HEK 293 cell membranes transiently expressing the hNK-3R (HEK 293-hNK-3R) or NK-4R (HEK 293-NK-4R), and functional studies (Ca2+ mobilization in the same cells) revealed a similar profile of sensitivity to tachykinin agonis ts and antagonists for both receptors; i.e., in binding studies with the hN K-3R, MePhe(7)-NKB > NKB > senktide >> NKA = Substance P; with the NK-4R, M ePhe(7)-NKB > NKB = senktide >> Substance P = NKA; and with antagonists, SB 223412 = SR 142801 > SB 222200 >> SR 48968 >> CP 99994 for both hNK-3R and NK-4R. Thus, the pharmacology of the two receptors was nearly identical. H owever, attempts to isolate or identify the NK-4R gene by using various mol ecular biological techniques were unsuccessful. Procedures, including neste d polymerase chain reaction studies, that used products with restriction en donuclease sites specific for either hNK-3R or NK-4R, failed to demonstrate the presence of NK-4R in genomic DNA from human, monkey, mouse, rat, hamst er, or guinea pig, and in cDNA libraries from human lung, brain, or heart, whereas the hNK-3R was detectable in the latter libraries. In view of the f ailure to demonstrate the presence of the putative NK-4R it is thought to b e premature to extend the current tachykinin receptor classification.