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 should 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 compared the pharmacological and molecular biological characteristics of the hNK-3R and NK-4R. Binding experiments, with (125)I-[MePhe(7)]-NKB binding to HEK 293 cell membranes transiently expressing the hNK-3R (HEK 293-hNK-3R) or NK-4R (HEK 293-NK-4R), and functional studies (Ca(2+) mobilization in the same cells) revealed a similar profile of sensitivity to tachykinin agonists and antagonists for both receptors; i.e., in binding studies with the hNK-3R, MePhe(7)-NKB > NKB > senktide >> NKA = Substance P; with the NK-4R, MePhe(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. However, attempts to isolate or identify the NK-4R gene by using various molecular biological techniques were unsuccessful. Procedures, including nested polymerase chain reaction studies, that used products with restriction endonuclease 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, hamster, 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 failure to demonstrate the presence of the putative NK-4R it is thought to be premature to extend the current tachykinin receptor classification.
Sarau
H M
HM
Department of Pulmonary Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Mooney
J L
JL
Schmidt
D B
DB
Foley
J J
JJ
Buckley
P T
PT
Giardina
G A
GA
Wang
D Y
DY
Lee
J A
JA
Hay
D W
DW
D001667:Binding, Competitive; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000032:analysis; D006801:Humans; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018039:Receptors, Tachykinin / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015183:Restriction Mapping; D015320:Tachykinins / Q000378:metabolism
D018076:DNA, Complementary; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D015320:Tachykinins; C102505:neurokinin receptor 4; D002118:Calcium