Neurotensin receptors (nomenclature as recommended by NC-IUPHAR [5]) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (NTS, 30990), which also generates neuromedin N, an agonist at the NTS₂ receptor. [³H]Neurotensin (human, mouse, rat) and [¹²⁵I]neurotensin (human, mouse, rat) may be used to label NTS₁ and NTS₂ receptors at 0.1-0.3 and 3-5 nM concentrations respectively.

Neurotensin (NTS, P30990) appears to be a low-efficacy agonist at the NTS₂ receptor [18], while the NTS₁ receptor antagonist meclinertant is an agonist at NTS₂ receptors [18]. An additional protein, provisionally termed NTS₃ (also known as NTR3, gp95 and sortilin; ENSG00000134243), has been suggested to bind lipoprotein lipase and mediate its degradation [14]. It has been reported to interact with the NTS₁ receptor [12] and the NTS₂ receptor [3], and has been implicated in hormone trafficking and/or neurotensin uptake. A splice variant of the NTS₂ receptor bearing 5 transmembrane domains has been identified in mouse [2] and later in rat [15]. The neurotensinergic system is implicated in various physiological and pathological processes related to neuropsychiatric and metabolic functions, cancer growth, food, and drug intake [9].

* Key recommended reading is highlighted with an asterisk

* Boules M, Li Z, Smith K, Fredrickson P, Richelson E. (2013) Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol (Lausanne), 4: 36. [PMID:23526754]

* Christou N, Blondy S, David V, Verdier M, Lalloué F, Jauberteau MO, Mathonnet M, Perraud A. (2020) Neurotensin pathway in digestive cancers and clinical applications: an overview. Cell Death Dis, 11 (12): 1027. [PMID:33268796]

* Mazella J, Béraud-Dufour S, Devader C, Massa F, Coppola T. (2012) Neurotensin and its receptors in the control of glucose homeostasis. Front Endocrinol (Lausanne), 3: 143. [PMID:23230428]

* Myers RM, Shearman JW, Kitching MO, Ramos-Montoya A, Neal DE, Ley SV. (2009) Cancer, chemistry, and the cell: molecules that interact with the neurotensin receptors. ACS Chem Biol, 4 (7): 503-25. [PMID:19462983]

* Ouyang Q, Zhou J, Yang W, Cui H, Xu M, Yi L. (2017) Oncogenic role of neurotensin and neurotensin receptors in various cancers. Clin Exp Pharmacol Physiol, 44 (8): 841-846. [PMID:28556374]

* Schroeder LE, Leinninger GM. (2018) Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders. Biochim Biophys Acta Mol Basis Dis, 1864 (3): 900-916. [PMID:29288794]

1. 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]

2. 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]

3. 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]

4. Choi KE, Hall CL, Sun JM, Wei L, Mohamad O, Dix TA, Yu SP. (2012) A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. FASEB J, 26 (7): 2799-810. [PMID:22459147]

5. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

6. Gully D, Labeeuw B, Boigegrain R, Oury-Donat F, Bachy A, Poncelet M, Steinberg R, Suaud-Chagny MF, Santucci V, Vita N et al.. (1997) Biochemical and pharmacological activities of SR 142948A, a new potent neurotensin receptor antagonist. J Pharmacol Exp Ther, 280 (2): 802-12. [PMID:9023294]

7. Hermans E, Geurts M, Maloteaux JM. (1997) Agonist and antagonist modulation of [35S]-GTP gamma S binding in transfected CHO cells expressing the neurotensin receptor. Br J Pharmacol, 121 (8): 1817-23. [PMID:9283723]

8. Hughes FM, Shaner BE, May LA, Zotian L, Brower JO, Woods RJ, Cash M, Morrow D, Massa F, Mazella J et al.. (2010) Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic. J Med Chem, 53 (12): 4623-32. [PMID:20481538]

9. Iyer MR, Kunos G. (2021) Therapeutic approaches targeting the neurotensin receptors. Expert Opin Ther Pat, 31 (5): 361-386. [PMID:33393392]

10. Labbé-Jullié C, Botto JM, Mas MV, Chabry J, Mazella J, Vincent JP, Gully D, Maffrand JP, Kitabgi P. (1995) [3H]SR 48692, the first nonpeptide neurotensin antagonist radioligand: characterization of binding properties and evidence for distinct agonist and antagonist binding domains on the rat neurotensin receptor. Mol Pharmacol, 47 (5): 1050-6. [PMID:7746272]

11. Li H, Hua T, Wang W, Wu X, Miao C, Huang W, Xiao Y, Yang J, Bradley JL, Peberdy MA et al.. (2019) The Effects of Pharmacological Hypothermia Induced by Neurotensin Receptor Agonist ABS 201 on Outcomes of CPR. Shock, 51 (5): 667-673. [PMID:30986796]

12. Martin S, Navarro V, Vincent JP, Mazella J. (2002) Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line. Gastroenterology, 123 (4): 1135-43. [PMID:12360476]

13. 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]

14. Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM. (1999) Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem, 274 (13): 8832-6. [PMID:10085125]

15. 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]

16. 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]

17. Skrzydelski D, Lhiaubet AM, Lebeau A, Forgez P, Yamada M, Hermans E, Rostene W, Pelaprat D. (2003) Differential involvement of intracellular domains of the rat NTS1 neurotensin receptor in coupling to G proteins: a molecular basis for agonist-directed trafficking of receptor stimulus. Mol Pharmacol, 64 (2): 421-9. [PMID:12869647]

18. 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]

19. Zhao Y, Wei ZZ, Lee JH, Gu X, Sun J, Dix TA, Wei L, Yu SP. (2020) Pharmacological hypothermia induced neurovascular protection after severe stroke of transient middle cerebral artery occlusion in mice. Exp Neurol, 325: 113133. [PMID:31770520]

Subcommittee members: Jean Mazella (Chairperson) Institut de Pharmacologie Moléculaire et Cellulaire Centre National de la Recherche Scientifique Unité Mixte de Recherche 7275 Valbonne 06560 France Philippe Sarret Department of Physiology and Biophysics Faculty of Medicine and Health Sciences Université de Sherbrooke Sherbrooke Quebec Canada

Other contributors: Jean-Pierre Vincent Institut de Pharmacologie Moléculaire et Cellulaire Unité Mixte de Recherche 6097 Centre National de la Recherche Scientifique Valbonne 06560 France