Neurotensin receptors: Introduction


The tridecapeptide neurotensin (NT) mediates its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS1, NTS2 and NTS3 (Sortilin 1). NTS1 and NTS2 belong to the 7 transmembrane domain/GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor. Therefore, the following introduction summarises only the properties of the two GPCRs NTS1 and NTS2.


Neurotensin, first isolated from bovine hypothalami by Carraway and Leeman in 1973 [9], was also found in the intestine. Classically, NT was synthesised from a precursor that contains another peptide, Neuromedin N, closely related to NT in terms of sequence and activity [11]. Cerebral administration of NT modulates dopaminergic transmission and leads to hypothermic and naloxone-independent analgesic responses. In the periphery, NT induces hypotension, decreases gastric acid secretion, activates lipid digestion and protects pancreatic beta cells from cytotoxic agent-induced apoptosis [8].

Receptor types

The existence of two distinct receptor sites for NT has been evidenced by ligand binding studies on rat brain synaptic membranes [19]: a high affinity NT binding site, later cloned as the NTS1 receptor, and a lower affinity NT binding site (sensitive to the H1 anti-histamine levocabastine), the NTS2 receptor.

NTS1 was first cloned from rat brain by Tanaka et al. [26]. Human NTS1 was cloned from the colonic adenocarcinoma cell line HT29 and shares 84% homology with the rat NTS1 receptor [27]. NT binds to these NTS1 receptors with an affinity of 0.1-0.4 nM, in comparison with 2-5 nM for NTS2. With regard to G protein-coupling, NTS1 is a Gq-preferring receptor since in almost all systems examined the binding of NT to NTS1 activated phospholipase C [1-2,13,16,21,25,29]. However, coupling of NTS1 to Gi/o and to Gs has been observed in some expression systems [3,7,13,15,21,30].

Activation of NTS1 is probably responsible for the observed effects of NT on cancer cell proliferation and food intake. However, the most convincing implication of NTS1 is related to the NT-dopamine interactions in the brain. Indeed, NT modulates dopamine transmisssion in the nigro-striatal and mesocorticolimbic pathways through NTS1, indicating that NT analogues specifically targeting this receptor might represent a new class of antipsychotic drugs.

NTS2 was cloned from mouse and rat brain [10,18] with the use of a NTS1 homology screening protocol. Human NTS2 was further cloned [28] and is 82% identical to the rat and mouse counterparts. Pharmacologically, mouse and rat NTS2 can be easily distinguished from other NT receptors by levocabastine, a histamine H1 antagonist, which totally and selectively inhibits the binding of NT to NTS2. Signal transduction of NTS2 is unclear because it depends on the cell system of expression used and on the receptor species. For example, NT activates mouse NTS2 when expressed in oocytes [5,18] but is unable to activate the same receptor expressed in HEK cells [4]. Rat NTS2 has been shown to be involved in NT-induced Erk1/2 phosphorylation by a mechanism that is dependent on receptor internalisation [14,24]. In contrast, human NTS2 can increase cytosolic calcium only when activated by the selective NTS1 antagonist SR48692, and NT has been shown to inhibit this effect as an antagonist [5,28]. The difficulty in studying the signal transduction mechanism of NTS2 certainly comes from its ability to be constitutively active [23].

NTS2 contributes in the protective effect of NT on pancreatic beta cells [8]. NTS2 has been described to be responsible for the analgesic response of centrally administered NT [12] . This observation is enhanced by the cerebral localisation of both its messenger RNA and its protein in structures implicated in the descending control of nociceptive imputs, especially in the periaqueductal gray and dorsal raphe. However, the expression of NTS2 immunoreactivity in areas devoid of neurotensinergic inputs indicates that NT might not be the exclusive endogenous ligand for NTS2.

Receptor structure

Although NTS2 belongs to the rhodopsin-like GPCR family, it has an unusual feature in its structure compared with those of NTS1 and other GPCRs. The Asp residue at position 2.50 in transmembrane helix 2 is a common characteristic of most rhodopsin-like GPCRs, including NTS1. For NTS2, the Asp residue is replaced by Ala79 in rat and mouse and by Gly79 in the human receptor. The absence of the Asp residue in helix 2 leads to a receptor that is much less sensitive to sodium ions [17]. Another special characteristic of the NTS2 is the absence of N-glycosylation sites in extracellular sequences. A splice variant corresponding to a deletion of 181 base pairs has been identified in the mouse and the rat brain [6,22]. The expressed protein is truncated to 281 amino acids and bears only five transmembrane domains. The rat splice variant binds NT with very poor affinity (10 μM) [22].

Receptor regulation and expression

The differential regulation of the mRNA for NTS1 by NT receptor agonists has been observed in several cell systems. The expression of NTS1 was found to be differentially regulated at the transcriptional and post-transcriptional levels, depending on the duration of exposure and the concentration of the agonist. Levels of mRNA encoding NTS2 are increased in astrocytes in response to a brain stab wound [20]. Agonist stimulation of NTS2 results in desensitization in the oocyte expression system [18].

NTS1 is expressed mainly in the brain and intestine. In the rat brain, high levels of NTS1 are found in neurons of the diagonal band of Broca, medial septal nucleus, magnocellular preoptic area, suprachiasmatic nucleus, substantia nigra and ventral tegmental area. NTS1 is selectively expressed by central dopamine neurons and is clearly associated with mesolimbic and mesocortical systems. NTS2 is essentially expressed in the brain. High densities of NTS2 are detected in the olfactory bulb, bed nucleus of the stria terminalis, amygdaloid complex, substantia nigra, ventral tegmental, and several brainstem nuclei. High levels of expression are also found in regions involved in descending control of nociception.


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1. Amar S, Kitabgi P, Vincent JP. (1986) Activation of phosphatidylinositol turnover by neurotensin receptors in the human colonic adenocarcinoma cell line HT29. FEBS Lett, 201 (1): 31-6. [PMID:3011505]

2. Amar S, Kitabgi P, Vincent JP. (1987) Stimulation of inositol phosphate production by neurotensin in neuroblastoma N1E115 cells: implication of GTP-binding proteins and relationship with the cyclic GMP response. J Neurochem, 49 (4): 999-1006. [PMID:3040912]

3. Amar S, Mazella J, Checler F, Kitabgi P, Vincent JP. (1985) Regulation of cyclic GMP levels by neurotensin in neuroblastoma clone N1E115. Biochem Biophys Res Commun, 129 (1): 117-25. [PMID:2988544]

4. Botto JM, Chabry J, Sarret P, Vincent JP, Mazella J. (1998) Stable expression of the mouse levocabastine-sensitive neurotensin receptor in HEK 293 cell line: binding properties, photoaffinity labeling, and internalization mechanism. Biochem Biophys Res Commun, 243 (2): 585-90. [PMID:9480852]

5. Botto JM, Guillemare E, Vincent JP, Mazella J. (1997) Effects of SR 48692 on neurotensin-induced calcium-activated chloride currents in the Xenopus oocyte expression system: agonist-like activity on the levocabastine-sensitive neurotensin receptor and absence of antagonist effect on the levocabastine insensitive neurotensin receptor. Neurosci Lett, 223 (3): 193-6. [PMID:9080465]

6. Botto JM, Sarret P, Vincent JP, Mazella J. (1997) Identification and expression of a variant isoform of the levocabastine-sensitive neurotensin receptor in the mouse central nervous system. FEBS Lett, 400 (2): 211-4. [PMID:9001400]

7. Bozou JC, Amar S, Vincent JP, Kitabgi P. (1986) Neurotensin-mediated inhibition of cyclic AMP formation in neuroblastoma N1E115 cells: involvement of the inhibitory GTP-binding component of adenylate cyclase. Mol Pharmacol, 29 (5): 489-96. [PMID:3010077]

8. Béraud-Dufour S, Coppola T, Massa F, Mazella J. (2009) Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells. Int J Biochem Cell Biol, 41 (12): 2398-402. [PMID:19891061]

9. Carraway R, Leeman SE. (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem, 248 (19): 6854-61. [PMID:4745447]

10. Chalon P, Vita N, Kaghad M, Guillemot M, Bonnin J, Delpech B, Le Fur G, Ferrara P, Caput D. (1996) Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett, 386 (2-3): 91-4. [PMID:8647296]

11. Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C. (1987) Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. Proc Natl Acad Sci USA, 84 (10): 3516-20. [PMID:3472221]

12. Dubuc I, Sarret P, Labbé-Jullié C, Botto JM, Honoré E, Bourdel E, Martinez J, Costentin J, Vincent JP, Kitabgi P et al.. (1999) Identification of the receptor subtype involved in the analgesic effect of neurotensin. J Neurosci, 19 (1): 503-10. [PMID:9870978]

13. Gailly P, Najimi M, Hermans E. (2000) Evidence for the dual coupling of the rat neurotensin receptor with pertussis toxin-sensitive and insensitive G-proteins. FEBS Lett, 483 (2-3): 109-13. [PMID:11042263]

14. Gendron L, Perron A, Payet MD, Gallo-Payet N, Sarret P, Beaudet A. (2004) Low-affinity neurotensin receptor (NTS2) signaling: internalization-dependent activation of extracellular signal-regulated kinases 1/2. Mol Pharmacol, 66 (6): 1421-30. [PMID:15361549]

15. Gilbert JA, Richelson E. (1984) Neurotensin stimulates formation of cyclic GMP in murine neuroblastoma clone N1E-115. Eur J Pharmacol, 99 (2-3): 245-6. [PMID:6329783]

16. Hermans E, Maloteaux JM, Octave JN. (1992) Phospholipase C activation by neurotensin and neuromedin N in Chinese hamster ovary cells expressing the rat neurotensin receptor. Brain Res Mol Brain Res, 15 (3-4): 332-8. [PMID:1331689]

17. Martin S, Botto JM, Vincent JP, Mazella J. (1999) Pivotal role of an aspartate residue in sodium sensitivity and coupling to G proteins of neurotensin receptors. Mol Pharmacol, 55 (2): 210-5. [PMID:9927610]

18. Mazella J, Botto JM, Guillemare E, Coppola T, Sarret P, Vincent JP. (1996) Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J Neurosci, 16 (18): 5613-20. [PMID:8795617]

19. Mazella J, Poustis C, Labbe C, Checler F, Kitabgi P, Granier C, van Rietschoten J, Vincent JP. (1983) Monoiodo-[Trp11]neurotensin, a highly radioactive ligand of neurotensin receptors. Preparation, biological activity, and binding properties to rat brain synaptic membranes. J Biol Chem, 258 (6): 3476-81. [PMID:6300046]

20. Nouel D, Sarret P, Vincent JP, Mazella J, Beaudet A. (1999) Pharmacological, molecular and functional characterization of glial neurotensin receptors. Neuroscience, 94 (4): 1189-97. [PMID:10625058]

21. Oury-Donat F, Thurneyssen O, Gonalons N, Forgez P, Gully D, Le Fur G, Soubrie P. (1995) Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non-neuronal cells. Br J Pharmacol, 116 (2): 1899-905. [PMID:8528577]

22. Perron A, Sarret P, Gendron L, Stroh T, Beaudet A. (2005) Identification and functional characterization of a 5-transmembrane domain variant isoform of the NTS2 neurotensin receptor in rat central nervous system. J Biol Chem, 280 (11): 10219-27. [PMID:15637074]

23. Richard F, Barroso S, Martinez J, Labbé-Jullié C, Kitabgi P. (2001) Agonism, inverse agonism, and neutral antagonism at the constitutively active human neurotensin receptor 2. Mol Pharmacol, 60 (6): 1392-8. [PMID:11723247]

24. Sarret P, Gendron L, Kilian P, Nguyen HM, Gallo-Payet N, Payet MD, Beaudet A. (2002) Pharmacology and functional properties of NTS2 neurotensin receptors in cerebellar granule cells. J Biol Chem, 277 (39): 36233-43. [PMID:12084713]

25. Snider RM, Forray C, Pfenning M, Richelson E. (1986) Neurotensin stimulates inositol phospholipid metabolism and calcium mobilization in murine neuroblastoma clone N1E-115. J Neurochem, 47 (4): 1214-8. [PMID:3018165]

26. Tanaka K, Masu M, Nakanishi S. (1990) Structure and functional expression of the cloned rat neurotensin receptor. Neuron, 4 (6): 847-54. [PMID:1694443]

27. Vita N, Laurent P, Lefort S, Chalon P, Dumont X, Kaghad M, Gully D, Le Fur G, Ferrara P, Caput D. (1993) Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor. FEBS Lett, 317 (1-2): 139-42. [PMID:8381365]

28. Vita N, Oury-Donat F, Chalon P, Guillemot M, Kaghad M, Bachy A, Thurneyssen O, Garcia S, Poinot-Chazel C, Casellas P et al.. (1998) Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Eur J Pharmacol, 360 (2-3): 265-72. [PMID:9851594]

29. Watson MA, Yamada M, Yamada M, Cusack B, Veverka K, Bolden-Watson C, Richelson E. (1992) The rat neurotensin receptor expressed in Chinese hamster ovary cells mediates the release of inositol phosphates. J Neurochem, 59 (5): 1967-70. [PMID:1328536]

30. Yamada M, Yamada M, Watson MA, Richelson E. (1993) Neurotensin stimulates cyclic AMP formation in CHO-rNTR-10 cells expressing the cloned rat neurotensin receptor. Eur J Pharmacol, 244 (1): 99-101. [PMID:8380559]

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