HGNC Approved Gene Symbol: NTSR1
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:62,708,836-62,762,771 (from NCBI)
The NTSR1 gene encodes a G protein-coupled receptor for neurotensin (NTS; 162650), a short peptide that functions both as a neurotransmitter and a hormone. NTSR1 signals preferentially through the Gq protein (see GNAQ; 600998) to mediate most of the effects of NTS (summary by White et al., 2012). See also NTSR2 (605538) and NTSR3 (SORT1; 602458).
The tridecapeptide neurotensin (162650) is widely distributed in various regions of the brain and in peripheral tissues. In the brain, neurotensin acts as a neuromodulator, in particular of dopamine transmission in the nigrostriatal and mesocorticolimbic systems, suggesting its possible implication in dopamine-associated behavioral neurodegenerative and neuropsychiatric disorders. Its various effects are mediated by specific membrane receptors. Vita et al. (1993) isolated a cDNA encoding a human neurotensin receptor (NTSR1) and showed that it predicts a 418-amino acid protein that shares 84% homology with the rat protein.
Vincent (1995) reviewed pharmacologic and molecular data suggesting the existence of other types of functional neurotensin receptors.
Le et al. (1997) cloned human NTSR1 cDNA and its genomic DNA. The authors stated that the neurotensin receptor has 7 transmembrane spanning regions and high homology to other receptors that couple to G proteins.
Using RT-PCR, immunofluorescence microscopy, and flow cytometric analysis, Saada et al. (2012) detected expression of NTS, NTSR1, NTSR2, and NTSR3 in primary human B lymphocytes and human B-cell lines at different stages of maturation. NTS exerted a proliferative and antiapoptotic effect on B cells. Patients with chronic B-cell lymphocytic leukemia (CLL; 151400) showed no expression of NTS and increased expression of NTSR2. Saada et al. (2012) concluded that NTS and its 2 specific receptors, NTSR1 and NTSR2, are expressed in human B lymphocytes, as previously found for T cells, macrophages, and dendritic cells, indicating that NTS may modulate immune responses and cell interactions.
Using knockdown and overexpression analyses, Law et al. (2016) showed that MIR133-alpha (see 610254) was involved in intracellular trafficking of NTR1 to plasma membrane in human colonic epithelial cells after NT exposure. MIR133-alpha regulated NTR1 trafficking through its binding target, AFTPH (619628). NT induced upregulation of MIR133-alpha through ZEB1 (189909), a negative transcriptional regulator of MIR133-alpha, in human colonic epithelial cells. Overexpression of AFTPH during NT stimulation reduced NTR1 translocation to early endosomes, an essential step for internalized NTR1 to be transported back to the plasma membrane. The MIR133-alpha/AFTPH axis controlled intracellular NTR1 trafficking by regulating expression of proteins related to endosome and TGN trafficking pathways. AFTPH overexpression promoted NTR1 retention in the cytosol during recovery from NT stimulation, but it did not affect NTR1 degradation in human colonic epithelial cells. Further analysis demonstrated that attenuation of NTR1 trafficking to plasma membrane in AFTPH-overexpressing cells was related to acidic condition of intracellular vesicles in the intracellular trafficking pathway during NTR1 translocation.
Crystal Structure
White et al. (2012) presented the crystal structure at 2.8-angstrom resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core.
Cryoelectron Microscopy
Kato et al. (2019) presented structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 (GNAI1; 139310) protein at a resolution of 3 angstroms. The authors identified 2 conformations: a canonical-state complex that is similar to G protein-coupled receptor (GPCR)-Gi/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a noncanonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the noncanonical state, NTSR1 exhibited features of both active and inactive conformations, which suggested that the structure may represent an intermediate form along the activation pathway of G proteins.
Huang et al. (2020) reported a cryoelectron microscopy structure of full-length human NTSR1 in complex with truncated human beta-arrestin-1 (107940) (beta-arr1(delta-CT)). Huang et al. (2020) found that phosphorylation of NTSR1 is critical for the formation of a stable complex with the truncated beta-arrestin form, and identified phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, Huang et al. (2020) observed a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin (180380)-arrestin-1 complex, in this structure arrestin is rotated by approximately 85 degrees relative to the receptor. Huang et al. (2020) concluded that their findings highlighted both conserved aspects and plasticity among arrestin-receptor interactions.
Le et al. (1997) determined that the NTSR1 gene contains 4 exons and spans more than 10 kb. The authors identified a highly polymorphic tetranucleotide repeat approximately 3 kb from the gene. Southern blot analysis revealed that the NTSR1 gene is present in the human genome as a single-copy gene.
Using fluorescence in situ hybridization with a human probe, Laurent et al. (1994) mapped the human NTSR1 gene to 20q13. Using a radiolabeled rat cDNA as a probe, they mapped the mouse neurotensin receptor gene to the H region of chromosome 2.
Huang, W., Masureel, M., Qu, Q., Janetzko, J., Inoue, A., Kato, H. E., Robertson, M. J., Nguyen, K. C., Glenn, J. S., Skiniotis, G., Kobilka, B. K. Structure of the neurotensin receptor 1 in complex with beta-arrestin 1. Nature 579: 303-308, 2020. [PubMed: 31945771] [Full Text: https://doi.org/10.1038/s41586-020-1953-1]
Kato, H. E., Zhang, Y., Hu, H., Suomivuori, C.-M., Kadji, F. M. N., Aoki, J., Krishna Kumar, K., Fonseca, R., Hilger, D., Huang, W., Latorraca, N. R., Inoue, A., Dror, R. O., Kobilka, B. K., Skiniotis, G. Conformational transitions of a neurotensin receptor 1-G(i1) complex. Nature 572: 80-85, 2019. [PubMed: 31243364] [Full Text: https://doi.org/10.1038/s41586-019-1337-6]
Laurent, P., Clerc, P., Mattei, M.-G., Forgez, P., Dumont, X., Ferrara, P., Caput, D., Rostene, W. Chromosomal localization of mouse and human neurotensin receptor genes. Mammalian Genome 5: 303-306, 1994. [PubMed: 8075503] [Full Text: https://doi.org/10.1007/BF00389545]
Law, I. K., Jensen, D., Bunnett, N. W., Pothoulakis, C. Neurotensin-induced miR-133-alpha expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci. Rep. 6: 22195, 2016. [PubMed: 26902265] [Full Text: https://doi.org/10.1038/srep22195]
Le, F., Groshan, K., Zeng, X. P., Richelson, E. Characterization of the genomic structure, promoter region, and a tetranucleotide repeat polymorphism of the human neurotensin receptor gene. J. Biol. Chem. 272: 1315-1322, 1997. [PubMed: 8995438] [Full Text: https://doi.org/10.1074/jbc.272.2.1315]
Saada, S., Marget, P., Fauchais, A.-L., Lise, M.-C., Chemin, G., Sindou, P., Martel, C., Delpy, L., Vidal, E., Jaccard, A., Troutaud, D., Lalloue, F., Jauberteau, M.-O. Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes. J. Immun. 189: 5293-5303, 2012. [PubMed: 23109725] [Full Text: https://doi.org/10.4049/jimmunol.1102937]
Vincent, J.-P. Neurotensin receptors: binding properties, transduction pathways, and structure. Cell. Molec. Neurobiol. 15: 501-512, 1995. [PubMed: 8719037] [Full Text: https://doi.org/10.1007/BF02071313]
Vita, N., Laurent, P., Lefort, S., Chalon, P., Dumont, X., Kaghad, M., Gully, D., Le Fur, G., Ferrara, P., Caput, D. Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor. FEBS Lett. 317: 139-142, 1993. [PubMed: 8381365] [Full Text: https://doi.org/10.1016/0014-5793(93)81509-x]
White, J. F., Noinaj, N., Shibata, Y., Love, J., Kloss, B., Xu, F., Gvozdenovic-Jeremic, J., Shah, P., Shiloach, J., Tate, C. G., Grisshammer, R. Structure of the agonist-bound neurotensin receptor. Nature 490: 508-513, 2012. [PubMed: 23051748] [Full Text: https://doi.org/10.1038/nature11558]