The neuropeptide, neurotensin, exerts numerous biological functions, including an efficient anti-apoptotic role, both in the central nervous system and in the periphery. This review summarizes studies that clearly evidenced the protective effect of neurotensin through its three known receptors. The pivotal involvement of the neurotensin receptor-3, also called sortilin, in the molecular mechanisms of the anti-apoptotic action of neurotensin has been analyzed in neuronal cell death, in cancer cell growth and in pancreatic beta cell protection. The relationships between the anti-apoptotic role of neurotensin and important physiological and pathological contexts are discussed in this review.
References
[1]
Carraway, R.; Leeman, S.E. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J. Biol. Chem. 1973, 248, 6854–6861.
[2]
Kitabgi, P. Differential processing of pro-neurotensin/neuromedin N and relationship to pro-hormone convertases. Peptides 2006, 27, 2508–2514, doi:10.1016/j.peptides.2006.03.038.
[3]
Goedert, M.; Emson, P.C. The regional distribution of neurotensin-like immunoreactivity in central and peripheral tissues of the cat. Brain Res. 1983, 272, 291–297, doi:10.1016/0006-8993(83)90576-0.
[4]
Uhl, G.R.; Snyder, S.H. Regional and subcellular distributions of brain neurotensin. Life Sci. 1976, 19, 1827–1832, doi:10.1016/0024-3205(76)90114-4.
Nemeroff, C.B.; Bissette, G.; Widerlov, E.; Beckmann, H.; Gerner, R.; Manberg, P.J.; Lindstrom, L.; Prange, A.J., Jr.; Gattaz, W.F. Neurotensin-Like immunoreactivity in cerebrospinal fluid of patients with schizophrenia, depression, anorexia nervosa-bulimia, and premenstrual syndrome. J. Neuropsychiatry Clin. Neurosci. 1989, 1, 16–20.
[10]
Breslin, N.A.; Suddath, R.L.; Bissette, G.; Nemeroff, C.B.; Lowrimore, P.; Weinberger, D.R. CSF concentrations of neurotensin in schizophrenia: An investigation of clinical and biochemical correlates. Schizophr. Res. 1994, 12, 35–41, doi:10.1016/0920-9964(94)90082-5.
[11]
Leeman, S.E.; Carraway, R.E. Neurotensin: Discovery, isolation, characterization, synthesis and possible physiological roles. Ann. N Y Acad. Sci. 1982, 400, 1–16, doi:10.1111/j.1749-6632.1982.tb31557.x.
[12]
Gui, X.; Carraway, R.E. Enhancement of jejunal absorption of conjugated bile acid by neurotensin in rats. Gastroenterology 2001, 120, 151–60.
[13]
Coppola, T.; Beraud-Dufour, S.; Antoine, A.; Vincent, J.P.; Mazella, J. Neurotensin protects pancreatic beta cells from apoptosis. Int. J. Biochem. Cell. Biol. 2008, 40, 2296–2302, doi:10.1016/j.biocel.2008.03.015.
[14]
Dolais-Kitabgi, J.; Kitabgi, P.; Brazeau, P.; Freychet, P. Effect of neurotensin on insulin, glucagon, and somatostatin release from isolated pancreatic islets. Endocrinology 1979, 105, 256–260, doi:10.1210/endo-105-1-256.
[15]
Beraud-Dufour, S.; Abderrahmani, A.; Noel, J.; Brau, F.; Waeber, G.; Mazella, J.; Coppola, T. Neurotensin is a regulator of insulin secretion in pancreatic beta-cells. Int. J. Biochem. Cell. Biol. 2010, 42, 1681–1688, doi:10.1016/j.biocel.2010.06.018.
[16]
Vincent, J.P.; Mazella, J.; Kitabgi, P. Neurotensin and neurotensin receptors. Trends Pharmacol. Sci. 1999, 20, 302–309, doi:10.1016/S0165-6147(99)01357-7.
[17]
Myers, R.M.; Shearman, J.W.; Kitching, M.O.; Ramos-Montoya, A.; Neal, D.E.; Ley, S.V. Cancer, chemistry, and the cell: Molecules that interact with the neurotensin receptors. ACS Chem. Biol. 2009, 4, 503–525, doi:10.1021/cb900038e.
[18]
Mazella, J.; Zsurger, N.; Navarro, V.; Chabry, J.; Kaghad, M.; Caput, D.; Ferrara, P.; Vita, N.; Gully, D.; Maffrand, J.P.; et al. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J. Biol. Chem. 1998, 273, 26273–26276.
[19]
Petersen, C.M.; Nielsen, M.S.; Nykjaer, A.; Jacobsen, L.; Tommerup, N.; Rasmussen, H.H.; Roigaard, H.; Gliemann, J.; Madsen, P.; Moestrup, S.K. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J. Biol. Chem. 1997, 272, 3599–3605.
[20]
Mazella, J. Sortilin/neurotensin receptor-3: A new tool to investigate neurotensin signaling and cellular trafficking? Cell. Signal. 2001, 13, 1–6, doi:10.1016/S0898-6568(00)00130-3.
[21]
Hermey, G. The Vps10p-domain receptor family. Cell. Mol. Life Sci. 2009, 66, 2677–2689, doi:10.1007/s00018-009-0043-1.
[22]
Kerr, J.F.; Winterford, C.M.; Harmon, B.V. Apoptosis. Its significance in cancer and cancer therapy. Cancer 1994, 73, 2013–2026, doi:10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J.
[23]
Hockenbery, D.; Nunez, G.; Milliman, C.; Schreiber, R.D.; Korsmeyer, S.J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990, 348, 334–336.
[24]
Korsmeyer, S.J. BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 1999, 59, 1693s–1700s.
[25]
Aouacheria, A.; Brunet, F.; Gouy, M. Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators. Mol. Biol. Evol. 2005, 22, 2395–2416.
[26]
Youle, R.J.; Strasser, A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell. Biol. 2008, 9, 47–59, doi:10.1038/nrm2308.
[27]
Chipuk, J.E.; Moldoveanu, T.; Llambi, F.; Parsons, M.J.; Green, D.R. The BCL-2 family reunion. Mol. Cell. 2010, 37, 299–310, doi:10.1016/j.molcel.2010.01.025.
[28]
Oltvai, Z.N.; Milliman, C.L.; Korsmeyer, S.J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993, 74, 609–619, doi:10.1016/0092-8674(93)90509-O.
[29]
Shen, Y.; White, E. p53-dependent apoptosis pathways. Adv. Cancer Res. 2001, 82, 55–84, doi:10.1016/S0065-230X(01)82002-9.
[30]
Gahete, M.D.; Rubio, A.; Cordoba-Chacon, J.; Gracia-Navarro, F.; Kineman, R.D.; Avila, J.; Luque, R.M.; Castano, J.P. Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer’s disease patients. J. Alzheimers Dis. 2010, 22, 819–828.
[31]
Jansen, P.; Giehl, K.; Nyengaard, J.R.; Teng, K.; Lioubinski, O.; Sjoegaard, S.S.; Breiderhoff, T.; Gotthardt, M.; Lin, F.; Eilers, A.; et al. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat. Neurosci. 2007, 10, 1449–1457.
[32]
Nykjaer, A.; Willnow, T.E. Sortilin: A receptor to regulate neuronal viability and function. Trends Neurosci. 2012, 35, 261–270.
[33]
Nykjaer, A.; Lee, R.; Teng, K.K.; Jansen, P.; Madsen, P.; Nielsen, M.S.; Jacobsen, C.; Kliemannel, M.; Schwarz, E.; Willnow, T.E.; et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 2004, 427, 843–848.
[34]
Al-Shawi, R.; Hafner, A.; Olsen, J.; Chun, S.; Raza, S.; Thrasivoulou, C.; Lovestone, S.; Killick, R.; Simons, P.; Cowen, T. Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system. Eur. J. Neurosci. 2008, 27, 2103–2114.
[35]
Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.Y.; Lee, F.S.; et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 2005, 25, 5455–5463.
[36]
Tauris, J.; Gustafsen, C.; Christensen, E.I.; Jansen, P.; Nykjaer, A.; Nyengaard, J.R.; Teng, K.K.; Schwarz, E.; Ovesen, T.; Madsen, P.; et al. Proneurotrophin-3 may induce Sortilin-dependent death in inner ear neurons. Eur. J. Neurosci. 2011, 33, 622–631.
[37]
Santos, A.M.; Lopez-Sanchez, N.; Martin-Oliva, D.; de la Villa, P.; Cuadros, M.A.; Frade, J.M. Sortilin participates in light-dependent photoreceptor degeneration in vivo. PLoS One 2012, 7, e36243.
[38]
Emmett, M.R.; Andren, P.E.; Caprioli, R.M. Specific molecular mass detection of endogenously released neuropeptides using in vivo microdialysis/mass spectrometry. J. Neurosci. Methods 1995, 62, 141–147, doi:10.1016/0165-0270(95)00070-4.
[39]
Holst Pedersen, J.; Fahrenkrug, J. Neurotensin-like immunoreactivities in human plasma: Feeding responses and metabolism. Peptides 1986, 7, 15–20, doi:10.1016/0196-9781(86)90054-9.
[40]
Li, H.B.; Lam, D.M. Synaptic organization of neurotensin immunoreactive amacrine cells in the chicken retina. J. Comp. Neurol. 1990, 294, 252–261, doi:10.1002/cne.902940209.
[41]
Bourcier, T.; Rondeau, N.; Paquet, S.; Forgez, P.; Lombet, A.; Pouzaud, F.; Rostene, W.; Borderie, V.; Laroche, L. Expression of neurotensin receptors in human corneal keratocytes. Invest. Ophthalmol. Vis. Sci. 2002, 43, 1765–1771.
[42]
Choi, K.E.; Hall, C.L.; Sun, J.M.; Wei, L.; Mohamad, O.; Dix, T.A.; Yu, S.P. A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. FASEB J. 2012, 26, 2799–2810, doi:10.1096/fj.11-201822.
[43]
Hughes, F.M., Jr.; Shaner, B.E.; May, L.A.; Zotian, L.; Brower, J.O.; Woods, R.J.; Cash, M.; Morrow, D.; Massa, F.; Mazella, J.; et al. 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. 2010, 53, 4623–4632.
[44]
Carraway, R.E.; Plona, A.M. Involvement of neurotensin in cancer growth: Evidence, mechanisms and development of diagnostic tools. Peptides 2006, 27, 2445–2460, doi:10.1016/j.peptides.2006.04.030.
[45]
Somai, S.; Gompel, A.; Rostene, W.; Forgez, P. Neurotensin counteracts apoptosis in breast cancer cells. Biochem. Biophys. Res. Commun. 2002, 295, 482–488, doi:10.1016/S0006-291X(02)00703-9.
[46]
Valerie, N.C.; Casarez, E.V.; Dasilva, J.O.; Dunlap-Brown, M.E.; Parsons, S.J.; Amorino, G.P.; Dziegielewski, J. Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation. Cancer Res. 2011, 71, 6817–6826.
[47]
Sumitomo, M.; Shen, R.; Nanus, D.M. Involvement of neutral endopeptidase in neoplastic progression. Biochim. Biophys. Acta 2005, 1751, 52–59, doi:10.1016/j.bbapap.2004.11.001.
[48]
Shipp, M.A.; Tarr, G.E.; Chen, C.Y.; Switzer, S.N.; Hersh, L.B.; Stein, H.; Sunday, M.E.; Reinherz, E.L. CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc. Natl. Acad. Sci. USA 1991, 88, 10662–10666.
[49]
D'Orleans-Juste, P.; Plante, M.; Honore, J.C.; Carrier, E.; Labonte, J. Synthesis and degradation of endothelin-1. Can. J. Physiol. Pharmacol. 2003, 81, 503–510, doi:10.1139/y03-032.
[50]
Checler, F.; Emson, P.C.; Vincent, J.P.; Kitabgi, P. Inactivation of neurotensin by rat brain synaptic membranes. Cleavage at the Pro10-Tyr11 bond by endopeptidase 24.11 (enkephalinase) and a peptidase different from proline-endopeptidase. J. Neurochem. 1984, 43, 1295–1301.
[51]
Assimakopoulos, S.F.; Scopa, C.D.; Zervoudakis, G.; Mylonas, P.G.; Georgiou, C.; Nikolopoulou, V.; Vagianos, C.E. Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice. Ann. Surg. 2005, 241, 159–167.
[52]
Assimakopoulos, S.F.; Alexandris, I.H.; Scopa, C.D.; Mylonas, P.G.; Thomopoulos, K.C.; Georgiou, C.D.; Nikolopoulou, V.N.; Vagianos, C.E. Effect of bombesin and neurotensin on gut barrier function in partially hepatectomized rats. World J. Gastroenterol. 2005, 11, 6757–6764.
[53]
Assimakopoulos, S.F.; Tsamandas, A.C.; Georgiou, C.D.; Vagianos, C.E.; Scopa, C.D. Bombesin and neurotensin exert antiproliferative effects on oval cells and augment the regenerative response of the cholestatic rat liver. Peptides 2010, 31, 2294–2303, doi:10.1016/j.peptides.2010.09.003.
[54]
Akcan, A.; Muhtaroglu, S.; Akgun, H.; Akyildiz, H.; Kucuk, C.; Sozuer, E.; Yurci, A.; Yilmaz, N. Ameliorative effects of bombesin and neurotensin on trinitrobenzene sulphonic acid-induced colitis, oxidative damage and apoptosis in rats. World J. Gastroenterol. 2008, 14, 1222–1230, doi:10.3748/wjg.14.1222.
[55]
Beraud-Dufour, S.; Coppola, T.; Massa, F.; Mazella, J. Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells. Int. J. Biochem. Cell. Biol. 2009, 41, 2398–2402, doi:10.1016/j.biocel.2009.04.002.
[56]
Fauchais, A.L.; Lalloue, F.; Lise, M.C.; Boumediene, A.; Preud'homme, J.L.; Vidal, E.; Jauberteau, M.O. Role of endogenous brain-derived neurotrophic factor and sortilin in B cell survival. J. Immunol. 2008, 181, 3027–3038.
[57]
Saada, S.; Marget, P.; Fauchais, A.L.; Lise, M.C.; Chemin, G.; Sindou, P.; Martel, C.; Delpy, L.; Vidal, E.; Jaccard, A.; et al. Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in Normal and malignant human B lymphocytes. J. Immunol. 2012, 189, 5293–5303, doi:10.4049/jimmunol.1102937.
[58]
Rogers, M.L.; Bailey, S.; Matusica, D.; Nicholson, I.; Muyderman, H.; Pagadala, P.C.; Neet, K.E.; Zola, H.; Macardle, P.; Rush, R.A. ProNGF mediates death of Natural Killer cells through activation of the p75NTR-sortilin complex. J. Neuroimmunol. 2010, 226, 93–103, doi:10.1016/j.jneuroim.2010.05.040.
[59]
Da Silva, L.; Neves, B.M.; Moura, L.; Cruz, M.T.; Carvalho, E. Neurotensin downregulates the pro-inflammatory properties of skin dendritic cells and increases epidermal growth factor expression. Biochim. Biophys. Acta 2011, 1813, 1863–1871.
[60]
Da Silva, L.; Carvalho, E.; Cruz, M.T. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin. Biol. Ther. 2010, 10, 1427–1439, doi:10.1517/14712598.2010.515207.
[61]
Cheung, N.S.; Pascoe, C.J.; Giardina, S.F.; John, C.A.; Beart, P.M. Micromolar L-glutamate induces extensive apoptosis in an apoptotic-necrotic continuum of insult-dependent, excitotoxic injury in cultured cortical neurones. Neuropharmacology 1998, 37, 1419–1429, doi:10.1016/S0028-3908(98)00123-3.
[62]
Ferraro, L.; Tomasini, M.C.; Siniscalchi, A.; Fuxe, K.; Tanganelli, S.; Antonelli, T. Neurotensin increases endogenous glutamate release in rat cortical slices. Life Sci. 2000, 66, 927–936.
[63]
Matsuyama, S.; Fukui, R.; Higashi, H.; Nishi, A. Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: Involvement of glutamate signalling. Eur. J. Neurosci. 2003, 18, 1247–1253, doi:10.1046/j.1460-9568.2003.02859.x.
[64]
Ferraro, L.; Tomasini, M.C.; Fernandez, M.; Bebe, B.W.; O’Connor, W.T.; Fuxe, K.; Glennon, J.C.; Tanganelli, S.; Antonelli, T. Nigral neurotensin receptor regulation of nigral glutamate and nigroventral thalamic GABA transmission: A dual-probe microdialysis study in intact conscious rat brain. Neuroscience 2001, 102, 113–120, doi:10.1016/S0306-4522(00)00448-6.
[65]
Ferraro, L.; Beggiato, S.; Tomasini, M.C.; Fuxe, K.; Tanganelli, S.; Antonelli, T. Neurotensin regulates cortical glutamate transmission by modulating N-methyl-D-aspartate receptor functional activity: An in vivo microdialysis study. J. Neurosci. Res. 2011, 89, 1618–1626, doi:10.1002/jnr.22686.
[66]
Allen, G.V.; Cheung, R.T.; Cechetto, D.F. Neurochemical changes following occlusion of the middle cerebral artery in rats. Neuroscience 1995, 68, 1037–1050, doi:10.1016/0306-4522(95)00198-R.
[67]
Katz, L.M.; Young, A.; Frank, J.E.; Wang, Y.; Park, K. Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia. Crit. Care. Med. 2004, 32, 806–810, doi:10.1097/01.CCM.0000114998.00860.FD.
[68]
Kokko, K.P.; Hadden, M.K.; Price, K.L.; Orwig, K.S.; See, R.E.; Dix, T.A. In vivo behavioral effects of stable, receptor-selective neurotensin [8–13] analogues that cross the blood-brain barrier. Neuropharmacology 2005, 48, 417–425, doi:10.1016/j.neuropharm.2004.10.008.
[69]
Antonelli, T.; Tomasini, M.C.; Fournier, J.; Mazza, R.; Tanganelli, S.; Pirondi, S.; Fuxe, K.; Ferraro, L. Neurotensin receptor involvement in the rise of extracellular glutamate levels and apoptotic nerve cell death in primary cortical cultures after oxygen and glucose deprivation. Cereb. Cortex 2008, 18, 1748–1757, doi:10.1093/cercor/bhm217.
[70]
Law, I.K.; Murphy, J.E.; Bakirtzi, K.; Bunnett, N.W.; Pothoulakis, C. Neurotensin-Induced proinflammatory signaling in human colonocytes is regulated by beta-arrestins and endothelin-converting enzyme-1-dependent endocytosis and resensitization of neurotensin receptor 1. J. Biol. Chem. 2012, 287, 15066–15075.
[71]
Martin, S.; Dicou, E.; Vincent, J.P.; Mazella, J. Neurotensin and the neurotensin receptor-3 in microglial cells. J. Neurosci. Res. 2005, 81, 322–326, doi:10.1002/jnr.20477.
[72]
Martin, S.; Navarro, V.; Vincent, J.P.; Mazella, J. Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line. Gastroenterology 2002, 123, 1135–1143.
