Neurotensin receptor 1

Neurotensin receptor type 1 (NTSR1) is a member of the class A G protein-coupled receptor (GPCR) superfamily, characterized by its canonical structure of seven transmembrane α-helices connected by extracellular and intracellular loops.{{cite journal | vauthors = Kitabgi P | title = Functional domains of the subtype 1 neurotensin receptor (NTS1) | journal = Peptides | volume = 27 | issue = 10 | pages = 2461–2468 | date = October 2006 | pmid = 16901586 | doi = 10.1016/j.peptides.2006.02.013 }} High-resolution crystal structures of NTSR1 have been determined in various functional states, including complexes with peptide agonists (such as the endogenous neurotensin fragment NTS8-13), non-peptide agonists, partial agonists, and antagonists, as well as in the ligand-free (apo) state.{{cite journal | vauthors = Deluigi M, Klipp A, Klenk C, Merklinger L, Eberle SA, Morstein L, Heine P, Mittl PR, Ernst P, Kamenecka TM, He Y, Vacca S, Egloff P, Honegger A, Plückthun A | title = Complexes of the neurotensin receptor 1 with small-molecule ligands reveal structural determinants of full, partial, and inverse agonism | journal = Science Advances | volume = 7 | issue = 5 | pages = eabe5504 | date = January 2021 | pmid = 33571132 | pmc = 7840143 | doi = 10.1126/sciadv.abe5504 | bibcode = 2021SciA....7.5504D }}{{cite journal | vauthors = White JF, Noinaj N, Shibata Y, Love J, Kloss B, Xu F, Gvozdenovic-Jeremic J, Shah P, Shiloach J, Tate CG, Grisshammer R | title = Structure of the agonist-bound neurotensin receptor | journal = Nature | volume = 490 | issue = 7421 | pages = 508–513 | date = October 2012 | pmid = 23051748 | pmc = 3482300 | doi = 10.1038/nature11558 | bibcode = 2012Natur.490..508W }}

The neurotensin binding pocket is located on the extracellular side of the receptor, where neurotensin binds in an extended conformation nearly perpendicular to the membrane, with the C-terminus oriented toward the receptor core. Key interactions involve charged residues in the binding pocket and the C-terminal arginine of neurotensin, while the receptor’s activation is associated with conformational changes that propagate from the ligand-binding site through the transmembrane helices to the intracellular side. The intracellular region of NTSR1 interacts with G proteins and β-arrestins, facilitating downstream signaling and receptor internalization; phosphorylation of specific intracellular sites is critical for stable β-arrestin binding.{{cite journal | vauthors = Huang W, Masureel M, Qu Q, Janetzko J, Inoue A, Kato HE, Robertson MJ, Nguyen KC, Glenn JS, Skiniotis G, Kobilka BK | title = Structure of the neurotensin receptor 1 in complex with β-arrestin 1 | journal = Nature | volume = 579 | issue = 7798 | pages = 303–308 | date = March 2020 | pmid = 31945771 | pmc = 7100716 | doi = 10.1038/s41586-020-1953-1 | bibcode = 2020Natur.579..303H }} Notably, the receptor also contains an amphipathic helix 8 following transmembrane helix 7, although its stability and presence may vary among different receptor states and constructs.{{cite journal | vauthors = Egloff P, Hillenbrand M, Klenk C, Batyuk A, Heine P, Balada S, Schlinkmann KM, Scott DJ, Schütz M, Plückthun A | title = Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 6 | pages = E655–E662 | date = February 2014 | pmid = 24453215 | pmc = 3926081 | doi = 10.1073/pnas.1317903111 | doi-access = free | bibcode = 2014PNAS..111E.655E }}

Neurotensin receptor 1, also called NTSR1, belongs to the large superfamily of G-protein coupled receptors and is considered a class-A GPCR. NTSR1 mediates multiple biological processes through modulation by neurotensin, such as low blood pressure, high blood sugar, low body temperature, antinociception, anti-neuronal damage {{cite journal | vauthors = Liu Q, Hazan A, Grinman E, Angulo JA | title = Pharmacological activation of the neurotensin receptor 1 abrogates the methamphetamine-induced striatal apoptosis in the mouse brain | journal = Brain Research | volume = 1659 | pages = 148–155 | date = 2017 | pmid = 28130052 | doi = 10.1016/j.brainres.2017.01.029 | s2cid = 6405660 }} and regulation of intestinal motility and secretion.

SBI-553 has demonstrated allosteric modulation potential via Beta-arrestin-2 signaling.{{Cite journal | vauthors = Chen O, Zhou Y, Bang S, Chandra S, Li Y, Chen G, Xie RG, He W, Xu J, Zhou R, Song S, Person KL, Moore MN, Alwin AR, Guo R | title = Arrestin-biased allosteric modulator of neurotensin receptor 1 alleviates acute and chronic pain | journal = Cell | date = May 2025 | pmid = 40393456 | doi = 10.1016/j.cell.2025.04.038 | url = https://linkinghub.elsevier.com/retrieve/pii/S0092867425005082 | language = en | url-access = subscription }}

The anti-nociceptive properties of NTSR1 has been shown to be modulated by SBI-810, an analog of SBI-553 via inhibition of NMDA receptor activity as well as extracellular-regulated signal kinase signaling in spinal cord neurons. SBI-810 outperformed gabapentin and oliceridine in reducing opioid-induced reduced conditioned place preference, guarding, and facial grimacing in mice, indicating superior mitigation of opioid withdrawal.

• ML314 – β-arrestin biased agonist{{cite journal | vauthors = Peddibhotla S, Hedrick MP, Hershberger P, Maloney PR, Li Y, Milewski M, Gosalia P, Gray W, Mehta A, Sugarman E, Hood B, Suyama E, Nguyen K, Heynen-Genel S, Vasile S, Salaniwal S, Stonich D, Su Y, Mangravita-Novo A, Vicchiarelli M, Roth GP, Smith LH, Chung TD, Hanson GR, Thomas JB, Caron MG, Barak LS, Pinkerton AB | title = Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor | journal = ACS Medicinal Chemistry Letters | volume = 4 | issue = 9 | pages = 846–851 | date = Jul 2013 | pmid = 24611085 | pmc = 3940307 | doi = 10.1021/ml400176n }}
• Neurotensin (NT1)

• Neurotensin receptor

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• {{cite journal | vauthors = Vincent JP | title = Neurotensin receptors: binding properties, transduction pathways, and structure | journal = Cellular and Molecular Neurobiology | volume = 15 | issue = 5 | pages = 501–512 | date = Oct 1995 | pmid = 8719037 | pmc = 11563118 | doi = 10.1007/BF02071313 | s2cid = 13335185 }}
• {{cite journal | vauthors = Vincent JP, Mazella J, Kitabgi P | title = Neurotensin and neurotensin receptors | journal = Trends in Pharmacological Sciences | volume = 20 | issue = 7 | pages = 302–309 | date = Jul 1999 | pmid = 10390649 | doi = 10.1016/S0165-6147(99)01357-7 }}
• {{cite journal | vauthors = Vita N, Laurent P, Lefort S, Chalon P, Dumont X, Kaghad M, Gully D, Le Fur G, Ferrara P, Caput D | title = Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor | journal = FEBS Letters | volume = 317 | issue = 1–2 | pages = 139–142 | date = Feb 1993 | pmid = 8381365 | doi = 10.1016/0014-5793(93)81509-X | s2cid = 5929592 | doi-access = free | bibcode = 1993FEBSL.317..139V }}
• {{cite journal | vauthors = Le F, Groshan K, Zeng XP, Richelson E | title = Characterization of the genomic structure, promoter region, and a tetranucleotide repeat polymorphism of the human neurotensin receptor gene | journal = The Journal of Biological Chemistry | volume = 272 | issue = 2 | pages = 1315–1322 | date = Jan 1997 | pmid = 8995438 | doi = 10.1074/jbc.272.2.1315 | doi-access = free }}
• {{cite journal | vauthors = Boudin H, Pélaprat D, Rostène W, Pickel VM, Beaudet A | title = Correlative ultrastructural distribution of neurotensin receptor proteins and binding sites in the rat substantia nigra | journal = The Journal of Neuroscience| volume = 18 | issue = 20 | pages = 8473–8484 | date = Oct 1998 | pmid = 9763490 | pmc = 6792847 | doi = 10.1523/JNEUROSCI.18-20-08473.1998 | doi-access = free }}
• {{cite journal | vauthors = Ye X, Mehlen P, Rabizadeh S, VanArsdale T, Zhang H, Shin H, Wang JJ, Leo E, Zapata J, Hauser CA, Reed JC, Bredesen DE | title = TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction | journal = The Journal of Biological Chemistry | volume = 274 | issue = 42 | pages = 30202–30208 | date = Oct 1999 | pmid = 10514511 | doi = 10.1074/jbc.274.42.30202 | doi-access = free }}
• {{cite journal | vauthors = Wang L, Friess H, Zhu Z, Graber H, Zimmermann A, Korc M, Reubi JC, Büchler MW | title = Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease | journal = Clinical Cancer Research| volume = 6 | issue = 2 | pages = 566–571 | date = Feb 2000 | pmid = 10690540 }}
• {{cite journal | vauthors = Cusack B, Jansen K, McCormick DJ, Chou T, Pang Y, Richelson E | title = A single amino acid of the human and rat neurotensin receptors (subtype 1) determining the pharmacological profile of a species-selective neurotensin agonist | journal = Biochemical Pharmacology | volume = 60 | issue = 6 | pages = 793–801 | date = Sep 2000 | pmid = 10930533 | doi = 10.1016/S0006-2952(00)00409-3 }}
• {{cite journal | vauthors = Oakley RH, Laporte SA, Holt JA, Barak LS, Caron MG | title = Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis* | journal = The Journal of Biological Chemistry | volume = 276 | issue = 22 | pages = 19452–19460 | date = Jun 2001 | pmid = 11279203 | doi = 10.1074/jbc.M101450200 | doi-access = free }}
• {{cite journal | vauthors = Leplatois P, Josse A, Guillemot M, Febvre M, Vita N, Ferrara P, Loison G | title = Neurotensin induces mating in Saccharomyces cerevisiae cells that express human neurotensin receptor type 1 in place of the endogenous pheromone receptor | journal = European Journal of Biochemistry | volume = 268 | issue = 18 | pages = 4860–4867 | date = Sep 2001 | pmid = 11559354 | doi = 10.1046/j.0014-2956.2001.02407.x | doi-access = free }}
• {{cite journal | vauthors = Lundquist JT, Büllesbach EE, Golden PL, Dix TA | title = Topography of the neurotensin (NT)(8-9) binding site of human NT receptor-1 probed with NT(8-13) analogs | journal = The Journal of Peptide Research| volume = 59 | issue = 2 | pages = 55–61 | date = Feb 2002 | pmid = 11906607 | doi = 10.1046/j.1397-002x.2001.10946.x }}
• {{cite journal | vauthors = Somaï S, Gompel A, Rostène W, Forgez P | title = Neurotensin counteracts apoptosis in breast cancer cells | journal = Biochemical and Biophysical Research Communications | volume = 295 | issue = 2 | pages = 482–488 | date = Jul 2002 | pmid = 12150975 | doi = 10.1016/S0006-291X(02)00703-9 }}
• {{cite journal | vauthors = Martin S, Navarro V, Vincent JP, Mazella J | title = Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line | journal = Gastroenterology | volume = 123 | issue = 4 | pages = 1135–1143 | date = Oct 2002 | pmid = 12360476 | doi = 10.1053/gast.2002.36000 | doi-access = free }}
• {{cite journal | vauthors = Toy-Miou-Leong M, Cortes CL, Beaudet A, Rostène W, Forgez P | title = Receptor trafficking via the perinuclear recycling compartment accompanied by cell division is necessary for permanent neurotensin cell sensitization and leads to chronic mitogen-activated protein kinase activation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 13 | pages = 12636–12646 | date = Mar 2004 | pmid = 14699144 | doi = 10.1074/jbc.M303384200 | doi-access = free }}
• {{cite journal | vauthors = Magazin M, Poszepczynska-Guigné E, Bagot M, Boumsell L, Pruvost C, Chalon P, Culouscou JM, Ferrara P, Bensussan A | title = Sezary syndrome cells unlike normal circulating T lymphocytes fail to migrate following engagement of NT1 receptor | journal = The Journal of Investigative Dermatology | volume = 122 | issue = 1 | pages = 111–118 | date = Jan 2004 | pmid = 14962098 | doi = 10.1046/j.0022-202X.2003.22131.x | doi-access = free }}
• {{cite journal | vauthors = Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC, Palù G, Castagliuolo I | title = Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 288 | issue = 4 | pages = G621–G629 | date = Apr 2005 | pmid = 15764810 | doi = 10.1152/ajpgi.00140.2004 }}

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• {{cite web | title = Neurotensin Receptors: NTS₁ | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=3004 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-05 | archive-date = 2012-04-02 | archive-url = https://web.archive.org/web/20120402212312/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=3004 | url-status = dead }}

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{{G protein-coupled receptors|g1}}

Category:G protein-coupled receptors