Review
Neurotensin and neurotensin receptors

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Abstract

Neurotensin is a brain and gastrointestinal peptide that fulfils many central and peripheral functions through its interaction with specific receptors. Three subtypes of neurotensin receptors have been cloned. Two of them belong to the family of G protein-coupled receptors, whereas the third one is an entirely new type of neuropeptide receptor and is identical to gp95/sortilin, a 100 kDa-protein with a single transmembrane domain. In this review, the present knowledge regarding the molecular and pharmacological properties of the three cloned neurotensin receptors is summarized and the relationship between these receptors and the known pharmacological effects of neurotensin is discussed.

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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