Trends in Pharmacological Sciences
ReviewNeurotensin and neurotensin receptors
Section snippets
NTS1 receptor
Initial indications about the existence of NT receptor subtypes have come from binding data. Membranes prepared from brain20 or gastrointestinal21 tissues generally contain two different classes of NT binding sites. The high-affinity sites (Kd=0.1–0.3 nm) are sensitive to Na+ ions and GTP, which decrease the affinity of the receptor for NT. The low-affinity sites (Kd=3–5 nm) are less sensitive to Na+ ions and insensitive to GTP. The antihistamine-1 drug levocabastine, which is devoid of any
nts2 receptor
As mentioned above, the existence of a levocabastine-sensitive receptor with a low affinity for NT was evident from binding data. The receptor protein corresponding to this binding activity (nts2) was cloned from rat16, mouse17 and human18 brain using a strategy based on sequence homology with the known NTS1 receptor. The rat and mouse nts2 (416 amino acids) are slightly longer than their human counterpart (410 amino acids). The three receptors all have the 7TM structure of G protein-coupled
Purification, cloning and identification to sortilin
The first indications about the existence of an NT receptor structurally unrelated to the NTS1 and nts2 receptors have come from purification studies. Brains of mouse56, rat, rabbit, horse, bovine and human57 contain high-affinity NT binding sites that can be solubilized in an active form by the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS). The ontogenic development, the binding properties and the molecular structure of the CHAPS-solubilized proteins bearing this
Mediation of NT functions by the three cloned receptors
Some of the pharmacological properties of NT have been ascribed to the selective activation of the NTS1 and nts2 receptors64. Intracerebroventricular injection in mice of antisense oligodeoxynucleotides directed against the nts2 decreases the nts2 mRNA and protein and concomitantly reduces NT-induced analgesia. This effect is specific in that the NTS1 levels are unaffected and sense or scramble oligodeoxynucleotides have no effect. In parallel experiments, NTS1-specific oligodeoxynucleotides
Concluding remarks
In 1996, a paper in this journal was entitled: The neurotensin receptor: is there more than one subtype?67. Today, this question can be answered in the affirmative. However, much progress remains to be done, in particular to define the physio-pathological roles associated with the three NT receptor subtypes that are the focus of this review. In this regard, it will be esssential to develop new pharmacological tools such as NT receptor agonists and antagonists specific for each class of
Chemical names
JMV449: H-Lysψ(CH2NH)-Lys-Pro-Tyr-Ile-Leu-OH
SR48692: 2-([1-{7-chloro-4-quinolinyl}-5-{2,6-dimethoxyphenyl}pyrazol-3-yl]carboxylamino)tricyclo(3.3.1.1.[3.7])decan-2-carboxylic acid
SR142948A: 2-(5,6-dimethylaminopropyl)-1-[4-{N-(3-dimethylaminopropyl)-N-methylcarbamoyl}-2-ispropylphenyl]-1H-pyrazole-3-carbonyl)aminoadamantane-2-carboxylic acid
Acknowledgements
We wish to thank all our collaborators P. Barbero, S. Barroso, J. N. Bidard, J. M. Botto, J. Chabry, F. Checler, C. Labbé-Jullié, S. Martin, V. Navarro, C. Rovère, P. Sarret and N. Zsürger for their extensive contribution to the work described in this review. We also thank Jacqueline Kervella for expert secretarial assistance and Franck Aguila for excellent artwork. This work was supported by the Centre National de la Recherche Scientifique and the Association pour la Recherche contre le Cancer.
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