Cellular and Molecular Neurobiology

, Volume 15, Issue 5, pp 501–512 | Cite as

Neurotensin receptors: Binding properties, transduction pathways, and structure

  • Jean-Pierre Vincent
Article

Summary

Neurotensin is a 13-amino acid peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) originally isolated from hypothalami (Carraway and Leeman, 1973) and later from intestines (Kitabgiet al., 1976) of bovine. The peptide is present throughout the animal kingdom, suggesting its participation to important processes basic to animal life (Carrawayet al., 1982). Neurotensin and its analogue neuromedin-N (Lys-Ile-Pro-Tyr-Ile-Leu) (Minaminoet al., 1984) are synthesized by a common precursor in mammalian brain (Kislauskiset al., 1988) and intestine (Dobneret al., 1987). The central and peripheral distribution and effects of neurotensin have been extensively studied. In the brain, neurotensin is exclusively found in nerve cells, fibers, and terminals (Uhlet al., 1979), whereas the majority of peripheral neurotensin is found in the endocrine N-cells located in the intestinal mucosa (Orciet al., 1976; Helmstaedteret al., 1977). Central or peripheral injections of neurotensin produce completely different pharmacological effects (Table I) indicating that the peptide does not cross the blood-brain barrier. Many of the effects of centrally administered neurotensin are similar to those of neuroleptics or can be antagonized by simultaneous administration of TRH (Table I). The recently discovered nonpeptide antagonist SR 48692 (Gullyet al., 1993) can inhibit several of the central and peripheral effects of neurotensin (Table I).

Like many other neuropeptides, neurotensin is a messenger of intracellular communication working as a neurotransmitter or neuromodulator in the brain (Nemeroffet al., 1982) and as a local hormone in the periphery (Hirsch Fernstromet al., 1980). Thus, several pharmacological, morphological, and neurochemical data suggest that one of the functions of neurotensin in the brain
is to regulate dopamine neurotransmission along the nigrostriatal and mesolimbic pathways (Quirion, 1983; Kitabgi, 1989). On the other hand, the likely role of neurotensin as a parahormone in the gastrointestinal tract has been well documented (Rosell and Rökaeus, 1981; Kitabgi, 1982).

Both central and peripheral modes of action of neurotensin imply as a first step the recognition of the peptide by a specific receptor located on the plasma membrane of the target cell. Formation of the neurotensin-receptor complex is then translated inside the cell by a change in the activity of an intracellular enzyme. This paper describes the binding and structural properties of neurotensin receptors as well as the signal transduction pathways that are activated by the peptide in various target tissues and cells.

Key words

neurotensin receptor binding transduction structure 

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References

  1. Al-Rodhann, N. R. F., Richelson, E., Gilbert, J. A., McCormick, D. J., Kanba, K. S., Pfenning, M. A., Larson, E. W., and Yaksh, T. L. (1991). Structure-antinociceptive activity of neurotensin and some novel analogues in the periaqueductal gray region of the brainstem.Brain Res. 557227–235.PubMedGoogle Scholar
  2. Amar, S., Mazella, J., Checler, F., Kitabgi, P., and Vincent, J. P. (1985). Regulation of cyclic GMP levels by neurotensin in neuroblastoma clone N1E115.Biochem. Biophys. Res. Commun. 129117–125.PubMedGoogle Scholar
  3. Amar, S., Kitabgi, P., and Vincent, J. P. (1986). Activation of phosphatidylinositol turnover by neurotensin receptors in the human colonic adenocarcinoma cell line HT29.FEBS Lett. 20131–36.PubMedGoogle Scholar
  4. Amar, S., Kitabgi, P., and Vincent, J. P. (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. 49999–1006.PubMedGoogle Scholar
  5. Bozou, J. C., Amar, S., Vincent, J. P., and 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. 29489–496.PubMedGoogle Scholar
  6. Bozou, J. C., Rochet, N., Magnaldo, I., Vincent, J. P., and Kitabgi, P. (1989). Neurotensin stimulates inositol trisphosphate-mediated calcium mobilization but not protein kinase C activation in HT29 cells. Involvement of a G protein.Biochem. J. 264871–878.PubMedGoogle Scholar
  7. Brun, P., Steinberg, R., Le Fur, G., and Soubrié, P. (1995). Blockade of neurotensin receptors by SR 48692 potentiates the facilitatory effect of haloperidol on the evokedin vivo dopamine release in the rat nucleus accumbens.J. Neurochem. 642073–2079.PubMedGoogle Scholar
  8. Carraway, R. E., and Leeman, S. E. (1973). The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami.J. Biol. Chem. 2486854–6861.PubMedGoogle Scholar
  9. Carraway, R., Ruane, S. E., and Hye-Ryeong, K. (1982). Distribution and immunochemical character of neurotensin-like material in representative vertebrates and invertebrates: Apparent conservation of the COOH-terminal region during evolution.Peptides 3115–123.PubMedGoogle Scholar
  10. Chabry, J., Gaudriault, G., Vincent, J. P., and Mazella, J. (1993). Implication of various forms of neurotensin receptors in the mechanism of internalization of neurotensin in cerebral neurons.J. Biol. Chem. 26817138–17144.PubMedGoogle Scholar
  11. Chabry, J., Labbé-Jullié, C., Gully, D., Kitabgi, P., Vincent, J. P., and Mazella, J. (1994). Stable expression of the cloned rat brain neurotensin receptor into fibroblasts: Binding properties, photoaffinity labeling, transduction mechanisms and internalization.J. Neurochem. 6319–27.PubMedGoogle Scholar
  12. Checler, F., Mazella, J., Kitabgi, P., and Vincent, J. P. (1986). High affinity receptor sites and rapid proteolytic inactivation of neurotensin in primary cultured neurons.J. Neurochem. 471742–1748.PubMedGoogle Scholar
  13. Cochrane, D. E., Feldberg, R. S., Miller, L. A., Carraway, R. E., and Barrocas, A. (1994). Inhibition of neurotensin (NT)-stimulated mast cell histamine secretion by NT-receptor(NT-R) antagonist and by pertussis toxin(PT): Evidence for a NT-R on the rat cell.Faseb J. 8:7 (Abs. 1195).Google Scholar
  14. Dobner, P. R., Barber, D. L., Villa-Komaroff, L., and McKierman, C. (1987). Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor.Proc. Natl. Acad. Sci. USA 843516–3520.PubMedGoogle Scholar
  15. Dubuc, I., Costentin, J., Terranova, J. P., Barnouin, M. C., Soubrié, P., Le Fur, G., Rostène, W., and Kitabgi, P. (1994). The nonpeptide neurotensin antagonist SR 48692 as a tool to reveal putative neurotensin receptor subtypes.Br. J. Pharmacol. 112352–354.PubMedGoogle Scholar
  16. Fostermann, U., Gorsky, L. D., Pollock, J. S., Ishii, K., Schmidt, H. H. H. W., Heller, M., and Murad, F. (1990). Hormone-induced biosynthesis of endothelium-derived relaxing factor/nitric oxide-like material in N1E-115 neuroblastoma cells requires calcium and calmodulin.Mol. Pharmacol. 387–13.PubMedGoogle Scholar
  17. Gaudriault, G., and Vincent, J. P. (1992). Selective labeling of α-or ε-amino groups in peptides by the Bolton-Hunter reagent.Peptides 131187–1192.PubMedGoogle Scholar
  18. Gilbert, J. A., and Richelson, E. (1984). Neurotensin stimulates formation of cyclic GMP in murine neuroblastoma clone N1E115.Eur. J. Pharmacol. 99245–246.PubMedGoogle Scholar
  19. Gilbert, J. A., Moses, C. J., Pfenning, M. A., and Richelson, E. (1986). Neurotensin and its analogs-Correlation of specific binding with stimulation of cylic GMP formation in neuroblastoma clone N1E115.Biochem. Pharmacol. 35391–397.PubMedGoogle Scholar
  20. Goedert, M., Pinnock, R. D., Downes, C. P., Mantyh, P. W., and Emson, P. C. (1984). Neurotensin stimulates inositol phospholipid hydrolysis in rat brain slices.Brain Res. 323193–197.PubMedGoogle Scholar
  21. Gully, D., Canton, M., Boigegrain, R., Jeanjean, F., Molimard, J. C., Poncelet, M., Gueudet, C., Heaulme, M., Leyris, R., Brouard, A., Pelaprat, D., Labbé-Jullié, C., Mazella, J., Soubrié, P., Maffrand, J. P., Rostène, W., Kitabgi, P., and Le Fur, G. (1993). Biochemical and pharmacological profile of a potent and selective non-peptide antagonist of neurotensin receptor.Proc. Natl. Acad. Sci. USA 9065–69.PubMedGoogle Scholar
  22. Helmstaedter, V., Feurle, G. E., and Forsmann, W. G. (1977). Ultrastructural identification of a new cell type—the N-cell as the source of neurotensin in the gut mucosa.Cell Tissue Res. 184445–452.PubMedGoogle Scholar
  23. Hermans, E., Maloteaux, J. M., and Octave, J. N. (1992). Phospholipase C activation by neurotensin and neuromedin N in chinese hamster ovary cells expressing the rat neurotensin receptor.Mol. Brain Res. 15332–338.PubMedGoogle Scholar
  24. Hirsch Fernstron, M., Carraway, R. E., and Leeman, S. E. (1980). Neurotensin. In Martini, L., and Ganong, W. F. (eds.),Front Neuroendocrinol., Raven Press, New York, pp. 103–127.Google Scholar
  25. Kasckow, J., and Nemeroff, C. B. (1991). The neurobiology of neurotensin: Focus on neurotensin-dopamine interactions.Regul. Pepti. 36153–164.Google Scholar
  26. Kislauskis, E., Bullock, B., McNeil, S., and Dobner, P. R. (1988). The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences.J. Biol. Chem. 2634963–4968.PubMedGoogle Scholar
  27. Kitabgi, P. (1982). Effects of neurotensin on intestinal smooth muscle: Application to the study of structure-activity relationships.Ann. N.Y. Acad. Sci. 40037–55.PubMedGoogle Scholar
  28. Kitabgi, P. (1989). Neurotensin modulates dopamine neurotransmission at several levels along brain dopaminergic pathways.Neurochem. Int. 14111–119.Google Scholar
  29. Kitabgi, P., Carraway, R. E., and Leeman, S. E. (1976). Isolation of a tridecapeptide from bovine intestinal tissue and its partial characterization as neurotensin.J. Biol. Chem. 2517053–7058.PubMedGoogle Scholar
  30. Kitabgi, P., Carraway, R. E., Van Rietschoten, J., Granier, C., Morgat, J. L., Menez, A., Leeman, S., and Freychet, P. (1977). Neurotensin: Specific binding to synaptic membranes from rat brain.Proc. Natl. Acad. Sci. USA 741846–1850.PubMedGoogle Scholar
  31. Kitabgi, P., Checler, F., Mazella, J., and Vincent, J. P. (1985). Pharmacology and biochemistry of neurotensin receptors.Rev. Basic Clin. Pharmacol. 5397–484.Google Scholar
  32. Kitabgi, P., Rostène, W., Dussaillant, M., Schotte, A., Laduron, P. M., and Vincent, J. P. (1987). Two populations of neurotensin binding sites in murine brain; discrimination by the antihistamine levocabastine reveals markedly different radioautographic distribution.Eur. J. Pharmacol. 140285–293.PubMedGoogle Scholar
  33. Labbé-Jullié, C., Dubuc, I., Brouard, A., Doulut, S., Bourdel, E., Pelaprat, D., Mazella, J., Martinez, J., Rostene, W., Costentin, J., and Kitabgi, P. (1994).In vivo andin vitro structure-activity studies with peptide and pseudopeptide neurotensin analogs suggest the existence of distinct central neurotensin receptor subtypes.J. Pharmacol. Exp. Ther. 268328–336.PubMedGoogle Scholar
  34. Lazarus, L. H., Perrin, M. H., and Brown, M. R. (1977). Mast cell binding of neurotensin. I. lodination of neurotensin and characterization of the interaction of neurotensin with mast cell receptor sites.J. Biol. Chem. 2527174–7179.PubMedGoogle Scholar
  35. Marsault, R., and Frelin, C. (1992). The activation by nitric oxide of guanylate cyclase in endothelial cells from brain capillaries.J. Neurochem. 59942–945.PubMedGoogle Scholar
  36. Mazella, J., Poustis, C., Labbé, C., Checler, F., Kitabgi, P., Granier, C., Van Rietschoeten, J., and Vincent, J. P. (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. 2583476–3481.PubMedGoogle Scholar
  37. Mazella, J., Chabry, J., Zsürger, N., and Vincent, J. P. (1989). Purification of the neurotensin receptor from mouse brain by affinity chromatography.J. Biol. Chem. 2645559–5563.PubMedGoogle Scholar
  38. Mazella, J., Chabry, J., Checler, F., Beaudet, A., and Vincent, J. P. (1993). Neurotensin receptors in primary culture of neurons. In Conn, M. P. (ed.),Methods in Neurosciences, Academic Press, pp. 334–351.Google Scholar
  39. McKinney, M., Bolden, C., Smith, C., Johnson, A., and Richelson, E. (1990). Selective blockade of receptor-mediated cyclic GMP formation in N1E-115 neuroblastoma cells by an inhibitor of nitric oxide synthesis.Eur. J. Pharmacol. 178139–140.PubMedGoogle Scholar
  40. Minamino, N., Kangawa, K., and Matsuo, H. (1984). Neuromedin N: a novel neurotensin-like peptide identified in porcine spinal cord.Biochem. Biophys. Res. Commun. 122542–549.PubMedGoogle Scholar
  41. Nemeroff, C. B., Luttinger, D., and Prange, A. J. (1982). Neurotensin and bombesin.Handbook Psychopharmacol. 16363–467.Google Scholar
  42. Nicot, A., Berod, A., Gully, D., Rowe, W., Quirion, R., De Kloet, E. R., and Rostène, W. (1994). Blockade of neurotensin binding in the rat hypothalamus and of the central action of neurotensin on the hypothalamic-pituitary-adrenal axis with non-peptide receptor antagonists.Neuroendocrinology 59572–578.PubMedGoogle Scholar
  43. Nisato, D., Guiraudou, P., Barthelemy, G., Gully, D., and Le Fur, G. (1994). SR 48692, a non peptide neurotensin receptor antagonist, blocks the cardiovascular effects elicited by neurotensin in guinea pigs.Life Sci. 5495–100.PubMedGoogle Scholar
  44. Orci, L., Baetens, O., Rufener, C., Brown, M., Vale, W., and Guillemin, R. (1976). Evidence for immunoreactive neurotensin in dog intestinal mucosa.Life Sci. 19559–562.PubMedGoogle Scholar
  45. Poncelet, M., Gueudet, C., Gully, D., Soubrié, P., and Le Fur, G. (1994). Turning behavior induced by intrastriatal injection of neurotensin in mice: Sensitivity to non-peptide neurotensin antagonists.Naunyn Schmiedeberg's Arch. Pharmacol. 60347–349.Google Scholar
  46. Poustis, C., Mazella, J., Kitabgi, P., and Vincent, J. P. (1984). High-affinity neurotensin binding sites in differentiated neuroblastoma N1E115 cells.J. Neurochem. 421094–1100.PubMedGoogle Scholar
  47. Prange, A. J. Jr. (1992). The manifold actions of neurotensin, a trophotropic agent.Ann. N.Y. Acad. Sci. 668298–306.PubMedGoogle Scholar
  48. Prange, A. J., Jr., and Nemeroff, C. B. (1982). The manifold actions of neurotensin: A first synthesis.Ann. N.Y. Acad. Sci. 400368–375.PubMedGoogle Scholar
  49. Pugsley, T. A., Akunne, H. C., Whetzel, S. Z., Demattos, S., Corbin, A. E., Wiley, J. N., Wustrow, D. J., Wisc, L. D., and Heffner, T. G. (1995). Differential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists.Peptides 1637–44.PubMedGoogle Scholar
  50. Quirion, R. (1983). Interactions between neurotensin and dopamine in the brain: An overview.Peptides 4609–614.PubMedGoogle Scholar
  51. Rosell, S., and Rökaeus, A. (1981). Actions and possible hormonal functions of circulating neurotensin.Clin. Physiol. 13–20.Google Scholar
  52. Sadoul, J. L., Mazella, J., Amar, S., Kitabgi, P., and Vincent, J. P. (1984). Preparation of neurotensin selectively iodinated on the tyrosine 3 residue. Biological activity and binding properties on mammalian neurotensin receptors.Biochem. Biophys. Res. Commun. 120812–819.PubMedGoogle Scholar
  53. Sato, M., Shiosaka, S., and Tohyama, M. (1991). Neurotensin and neuromedin N elevate the cytosolic calcium concentration via transiently appearing neurotensin binding sites in cultured rat cortex cells.Development. Brain Res. 5897–103.Google Scholar
  54. Schaeffer, P., Laplace, M. C., Savi, P., Pflieger, A. M., Gully, D., and Herbert, J. M. (1995). Human umbilical vein endothelial cells express high affinity neurotensin receptors coupled to intracellular calcium release.J. Biol. Chem. 2703409–3413.PubMedGoogle Scholar
  55. Schotte, A., and Laduron, P. M. (1987). Different postnatal ontogeny of two 3H neurotensin binding sites in rat brain.Brain Res. 408326–328.PubMedGoogle Scholar
  56. Schotte, A., Leysen, J. E., and Laduron, P. M. (1986). Evidence for a displaceable non-specific 3H neurotensin binding site in rat brain.Naunyn-Schmiedeberg's Arch. Pharmacol. 333400–405.Google Scholar
  57. Schotte, A., Rostène, W., and Laduron, P. M. (1988). Different subcellular localization of neurotensin-receptor and neurotensin-acceptor sites in the rat brain dopaminergic system.J. Neurochem. 501026–1031.PubMedGoogle Scholar
  58. Shi, W. X., and Bunney, B. S. (1992). Role of intracellular cAMP and protein kinase A in the actions of dopamine and neurotensin on midbrain dopamine neurons.J. Neurosci. 122433–2438.PubMedGoogle Scholar
  59. Snider, R. M., Forray, C., Pfenning, M., and Richelson, E. (1986). Neurotensin stimulates inositol phospholipid metabolism and calcium mobilization in murine neuroblastoma clone N1E115.J. Neurochem. 471214–1218.PubMedGoogle Scholar
  60. Steinberg, R., Brun, P., Fournier, M., Souilhac, J., Rodier, D., Mons, G., Terranova, J. P., Le Fur, G., and Soubrié, P. (1994). SR 48692, a non-peptide neurotensin receptor antagonist differentially affects neurotensin-induced behaviour and changes in dopaminergic transmission.Neuroscience 59921–929.PubMedGoogle Scholar
  61. Tanaka, K., Masu, M., and Nakanishi, S. (1990). Structure and functional expression of the cloned rat neurotensin receptor.Neuron 4847–854.PubMedGoogle Scholar
  62. Turner, J. T., James-Kracke, M. R., and Camden, J. M. (1990). Regulation of the neurotensin receptor and intracellular calcium mobilization in HT29 cells.J. Pharmacol. Exp. Ther. 2531049–1056.PubMedGoogle Scholar
  63. Uhl, G. R., Bennett, J. P., and Snyder, S. H. (1977). Neurotensin, a central nervous system peptide: Apparent receptor binding in brain membranes.Brain Res. 130299–313.PubMedGoogle Scholar
  64. Uhl, G. R., Goodman, R. R., and Snyder, S. H. (1979). Neurotensin-containing cell bodies, fibers and nerve terminals in the brainstern of the rat: immunohistochemical mapping.Brain Res. 16777–91.PubMedGoogle Scholar
  65. Vincent, J. P., Mazella, J., Chabry, J., and Zsürger, N. (1990). The neurotensin receptor from mammalian brain: Solubilization and purification by affinity chromatography. In Litwack, G. (eds.),Receptor Purification, Humana Press, pp. 131–145.Google Scholar
  66. Vita, N., Laurent, P., Lefort, S., Chalon, P., Dumont, X., Kaghad, M., Gully, D., Le Fur, G., Ferrara, P., and Caput, D. (1993). Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor.FEBS Lett. 317139–142.PubMedGoogle Scholar
  67. Wagstaff, J. D., Bush, L. G., Gibb, J. W., and Hanson, G. R. (1994). Endogenous neurotensin antagonizes methamphetamine-enhanced dopaminergic activity.Brain Res. 665237–244.PubMedGoogle Scholar
  68. Watson, M. A., Yamada, M., Yamada, M., Cusack, B., Veverka, K., Bolden-Watson, C., and Richelson, E. (1992). The rat neurotensin receptor expressed in chinese hamster ovary cells mediates the release of inositol phosphates.J. Neurochem. 591967–1970.PubMedGoogle Scholar
  69. Yamada, M., Yamada, M., Watson, M. A., and Richelson, E. (1993). Neurotensin stimulates cyclic AMP formation in CHO-rNTR-10 cells expressing the cloned rat neurotensin receptor.Eur. J. Pharmacol. 24499–101.PubMedGoogle Scholar
  70. Zsürger, N., Chabry, J., Coquerel, A., and Vincent, J. P. (1992). Ontogenesis and binding properties of high affinity neurotensin receptors in human brain.Brain Res. 586303–310.PubMedGoogle Scholar
  71. Zsürger, N., Mazella, J., and Vincent, J. P. (1994). Solubilization and purification of a high affinity neurotensin receptors from new born human brain.Brain Res. 639245–252.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Jean-Pierre Vincent
    • 1
  1. 1.IPMC-CNRS UPR 411ValbonneFrance

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