Neurotensin receptor type 1 (NTSR1) is a member of the class AG protein-coupled receptor (GPCR) superfamily, characterized by its canonical structure of seven transmembraneα-helices connected by extracellular and intracellular loops.[8] 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.[9][10]
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.[10] 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.[9] The intracellular region of NTSR1 interacts withG proteins andβ-arrestins, facilitating downstream signaling and receptor internalization;phosphorylation of specific intracellular sites is critical for stable β-arrestin binding.[11] 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.[12]
Neurotensin receptor 1, also called NTSR1, belongs to the large superfamily ofG-protein coupled receptors and is considered a class-A GPCR. NTSR1 mediates multiple biological processes through modulation byneurotensin, such aslow blood pressure,high blood sugar,low body temperature, antinociception, anti-neuronal damage[13] and regulation of intestinal motility and secretion.[6]
SBI-553 is an intracellularallosteric modulator that promotes β-arrestin recruitment but not canonical Gq signaling.[14] SBI-553 exerts β-arrestin-dependent effects on rodent behavior.[15]
Theanti-nociceptive properties of NTSR1 has been shown to be modulated by SBI-810, an analog of SBI-553 via inhibition ofNMDA receptor activity as well asextracellular-regulated signal kinase signaling in spinal cord neurons.[15] SBI-810 outperformedgabapentin andoliceridine in reducing opioid-induced reduced conditioned place preference, guarding, and facial grimacing in mice, indicating superior mitigation of opioid withdrawal.
^Liu Q, Hazan A, Grinman E, Angulo JA (2017). "Pharmacological activation of the neurotensin receptor 1 abrogates the methamphetamine-induced striatal apoptosis in the mouse brain".Brain Research.1659:148–155.doi:10.1016/j.brainres.2017.01.029.PMID28130052.S2CID6405660.
Vincent JP, Mazella J, Kitabgi P (Jul 1999). "Neurotensin and neurotensin receptors".Trends in Pharmacological Sciences.20 (7):302–309.doi:10.1016/S0165-6147(99)01357-7.PMID10390649.
Wang L, Friess H, Zhu Z, Graber H, Zimmermann A, Korc M, et al. (Feb 2000). "Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease".Clinical Cancer Research.6 (2):566–571.PMID10690540.
Cusack B, Jansen K, McCormick DJ, Chou T, Pang Y, Richelson E (Sep 2000). "A single amino acid of the human and rat neurotensin receptors (subtype 1) determining the pharmacological profile of a species-selective neurotensin agonist".Biochemical Pharmacology.60 (6):793–801.doi:10.1016/S0006-2952(00)00409-3.PMID10930533.
Lundquist JT, Büllesbach EE, Golden PL, Dix TA (Feb 2002). "Topography of the neurotensin (NT)(8-9) binding site of human NT receptor-1 probed with NT(8-13) analogs".The Journal of Peptide Research.59 (2):55–61.doi:10.1046/j.1397-002x.2001.10946.x.PMID11906607.
Somaï S, Gompel A, Rostène W, Forgez P (Jul 2002). "Neurotensin counteracts apoptosis in breast cancer cells".Biochemical and Biophysical Research Communications.295 (2):482–488.doi:10.1016/S0006-291X(02)00703-9.PMID12150975.
"Neurotensin Receptors: NTS1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2012-04-02. Retrieved2008-12-05.
