Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells.
The human levocabastine-sensitive neurotensin NT2 receptor was cloned from a cortex cDNA library and stably expressed in Chinese hamster ovary (CHO) cells in order to study its binding and signalling characteristics. The receptor binds neurotensin as well as several other ligands already described for neurotensin NT1 receptor. It also binds levocabastine, a histamine H1 receptor antagonist that is not recognised by neurotensin NT1 receptor. Neurotensin binding to recombinant neurotensin NT2 receptor expressed in CHO cells does not elicit a biological response as determined by second messenger measurements. Levocabastine, and the peptides neuromedin N and xenin were also ineffective on neurotensin NT2 receptor activation. Experiments with the neurotensin NT1 receptor antagonists SR48692 and SR142948A, resulted in the unanticipated discovery that both molecules are potent agonists on neurotensin NT2 receptor. Both compounds, following binding to neurotensin NT2 receptor, enhance inositol phosphates (IP) formation with a subsequent [Ca2+]i mobilisation; induce arachidonic acid release; and stimulate mitogen-activated protein kinase (MAPK) activity. Interestingly, these activities are antagonised by neurotensin and levocabastine in a concentration-dependent manner. These activities suggest that the human neurotensin NT2 receptor may be of physiological importance and that a natural agonist for the receptor may exist.
Vita
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Sanofi Recherche, Labège, France.
Oury-Donat
F
F
Chalon
P
P
Guillemot
M
M
Kaghad
M
M
Bachy
A
A
Thurneyssen
O
O
Garcia
S
S
Poinot-Chazel
C
C
Casellas
P
P
Keane
P
P
Le Fur
G
G
Maffrand
J P
JP
Soubrie
P
P
Caput
D
D
Ferrara
P
P
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000032:analysis; D006801:Humans; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution
D018076:DNA, Complementary; C490985:NTSR2 protein, human; D012333:RNA, Messenger; D018028:Receptors, Neurotensin; D011994:Recombinant Proteins; C114036:neurotensin type 1 receptor; D009496:Neurotensin