Neurotensin
| neurotensin | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | pro-neurotensin/neuromedinneurotensin/neuromedin NNTNTS(151-163) | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | GeneCards:[1];OMA:- orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Neurotensin/neuromedin N precursor | |||||||||
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| Identifiers | |||||||||
| Symbol | Pro-NT_NN | ||||||||
| Pfam | PF07421 | ||||||||
| InterPro | IPR008055 | ||||||||
| OPM superfamily | 257 | ||||||||
| OPM protein | 2oyv | ||||||||
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3D model (JSmol)
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| Properties | |
| C78H121N21O20 | |
| Molar mass | 1672.92 |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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Neurotensinis a 13amino acidneuropeptidethat is implicated in the regulation ofluteinizing hormoneandprolactinrelease and has significant interaction with thedopaminergic system.Neurotensin was first isolated from extracts ofbovinehypothalamusbased on its ability to cause a visiblevasodilationin the exposedcutaneousregions of anesthetized rats.[1]
Neurotensin is distributed throughout the central nervous system, with highest levels in thehypothalamus,amygdalaandnucleus accumbens.It induces a variety of effects, including analgesia, hypothermia and increased locomotor activity. It is also involved inregulationof dopamine pathways. In the periphery, neurotensin is found inenteroendocrine cellsof the small intestine, where it leads tosecretionandsmooth musclecontraction.[2]
Sequence and biosynthesis[edit]
Neurotensin shares significant sequence similarity in its 6C-terminalamino acidswith several other neuropeptides, includingneuromedin N(which is derived from the same precursor). This C-terminal region is responsible for the fullbiological activity,theN-terminalportion having a modulatory role. The neurotensin/neuromedin Nprecursorcan also be processed to produce large 125–138amino acidpeptideswith the neurotensin or neuromedin Nsequenceat their C terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lastingactivatorsin a number of pathophysiological situations.
The sequence of bovine neurotensin was determined to be pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH.[3]Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptideneuromedin N.[4][5]The peptide coding domains are located in tandem near thecarboxyl terminalend of theprecursorand are bounded and separated by paired basicamino acid(lysine-arginine) processing sites.
Clinical significance[edit]
Neurotensin is a potentmitogenforcolorectal cancer.[6]
Neurotensin has been implicated in the modulation ofdopaminesignaling, and produces a spectrum of pharmacological effects resembling those ofantipsychotic drugs,leading to the suggestion that neurotensin may be an endogenousneuroleptic.Neurotensin-deficient mice display defects in responses to several antipsychotic drugs consistent with the idea that neurotensin signaling is a key component underlying at least some antipsychotic drug actions.[7]These mice exhibit modest defects inprepulse inhibition(PPI) of thestartle reflex,a model that has been widely used to investigate antipsychotic drug action in animals. Antipsychotic drug administration augments PPI under certain conditions. Comparisons between normal and neurotensin-deficient mice revealed striking differences in the ability of different antipsychotic drugs to augment PPI. While the atypical antipsychotic drug clozapine augmented PPI normally in neurotensin-deficient mice, the conventional antipsychotichaloperidoland the newer atypical antipsychoticquetiapinewere ineffective in these mice, in contrast to normal mice where these drugs significantly augmented PPI. These results suggest that certain antipsychotic drugs require neurotensin for at least some of their effects. Neurotensin-deficient mice also display defects in striatal activation following haloperidol, but notclozapineadministration in comparison to normal wild type mice, indicating that striatal neurotensin is required for the full spectrum of neuronal responses to a subset of antipsychotic drugs.[8]
Neurotensin is an endogenous neuropeptide involved inthermoregulationthat can inducehypothermiaandneuroprotectionin experimental models ofcerebral ischemia.[9]
Gene expression[edit]
Neurotensin gene expression has been shown to be modulated byestrogenin both human SK-N-SHneuroblastomacell cultures as well as in mice through interactions withcyclic AMP(cAMP) signaling. Specifically, estrogen increased cAMP activity and cAMP response element-binding proteinphosphorylationin neuroblastoma cells prior to the induction of neurotensin genetranscription.Additionally, neurotensin gene transcription was blocked inknock-out micelacking the RIIβ subunit of theprotein kinase Aholoenzyme. These findings may indicate mechanisms of cross-talk signaling in brain hormone activity and expression of hormone-related genes.[10]Other sex hormone-related changes in neurotensin expression have been associated with activity in thepreoptic area.In female rats, neurotensin expression was shown to be at its highest in the medial preoptic area (mPOA) during the proestrus phase of theestrous cycle.[11]
Altered expression of neurotensin genes as well as neurotensin receptor genes have been exhibited in postpartum female mice. Whileneurotensin receptor 1(Ntsr1) mRNA in theparaventricular nucleus of the hypothalamus(PVN) was lowered, neurotensin, but not neurotensin mRNA, was shown to be higher in the PVN. Neurotensin mRNA as well as the peptide itself were also expressed higher in the medial preoptic area (mPOA). These expression patterns were not shown in the virgin female control group, and align with other research implicating neurotensin gene expression variation in the regulation of maternal behaviors.[12]
Other patterns of neurotensin expression related to the medial preoptic area show relation to the modulation of social reward. Analysis of neurotensin gene-labelled neurons revealed that neurotensin-containing neuronal projections from the mPOA to theventral tegmental area(VTA) in mice were associated with the encoding of odor cues as well as social attraction, further implicating neurotensin in hormonal as well as reward signaling.[13]
Neurotensin has also been implicated in learning processes. A study examining song development in male zebra finches showed variations in neurotensin andneurotensin receptorgene expression across different stages of song development. The early stage of transition between sensory and sensorimotor periods was marked by decreases in both neurotensin and neurotensin receptor mRNA expression, which may indicate a role of neurotensin in initiating sensorimotor learning. During the sensorimotor subsong stage, neurotensin gene expression and neurotensin receptor 1 (Ntsr1) gene expression exhibited complementary expression patterns in song-related brain regions, which may indicate changes in neuronal responses to neurotensin across development.[14]
Neurotensin also plays a role in peripheral tissues outside of the nervous system, mainly in the gastrointestinal tract, and has been implicated in cancer development. DNA promotermethylationhas been shown to be a major regulator in the expression of neurotensin receptor 1 and 2 genes in colorectal cancer cells. Additionally, knock-down of the NTSR1 gene as well as treatment with a NTSR1antagonistinhibited colorectal cancer cell proliferation and migration.[15]Leiomyomasor fibroid tumors in uterine tissue have also been associated with higher expression of neurotensin and NTSR1.[16]
See also[edit]
References[edit]
- ^Carraway R, Leeman SE (1973)."The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami".J. Biol. Chem.248(19): 6854–61.doi:10.1016/S0021-9258(19)43429-7.PMID4745447.
- ^Friry C, Feliciangeli S, Richard F, Kitabgi P, Rovere C (February 2002). "Production of recombinant large proneurotensin/neuromedin N-derived peptides and characterization of their binding and biological activity".Biochem. Biophys. Res. Commun.290(4): 1161–8.doi:10.1006/bbrc.2001.6308.PMID11811984.
- ^Carraway R, Leeman SE (1975)."The amino acid sequence of a hypothalamic peptide, neurotensin".J. Biol. Chem.250(5): 1907–11.doi:10.1016/S0021-9258(19)41780-8.PMID1167549.
- ^Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C (1987)."Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor".Proc. Natl. Acad. Sci. U.S.A.84(10): 3516–20.Bibcode:1987PNAS...84.3516D.doi:10.1073/pnas.84.10.3516.PMC304902.PMID3472221.
- ^Kislauskis E, Bullock B, McNeil S, Dobner PR (1988)."The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences".J. Biol. Chem.263(10): 4963–8.doi:10.1016/S0021-9258(18)68881-7.PMID2832414.
- ^Wang X, Wang Q, Ives KL, Evers BM (September 2006)."Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells".Clin. Cancer Res.12(18): 5346–55.doi:10.1158/1078-0432.CCR-06-0968.PMC2613866.PMID17000667.
- ^Kinkead, B, Dobner PR, Egnatashvili, V, Murray, T, Deitemeyer, N, Nemeroff, CB (2005)."Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but no haloperidol, olanzapine, or quetiapine".J. Pharmacol. Exp. Ther.315(1): 256–264.doi:10.1124/jpet.105.087437.PMID15987829.S2CID15095566.
{{cite journal}}:CS1 maint: multiple names: authors list (link) - ^Dobner, PR, Fadel, J, Deitemeyer, N, Carraway, RE, Deutch, AY (2001)."Neurotensin-deficient mice show altered responses to antipsychotic drugs".Proc. Natl. Acad. Sci. USA.98(14): 8048–8053.Bibcode:2001PNAS...98.8048D.doi:10.1073/pnas.141042198.PMC35465.PMID11427716.
{{cite journal}}:CS1 maint: multiple names: authors list (link) - ^Katz LM, Young A, Frank JE, Wang Y, Park K (March 2004). "Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia".Crit. Care Med.32(3): 806–10.doi:10.1097/01.CCM.0000114998.00860.FD.PMID15090966.S2CID41533372.
- ^Watters, Jyoti J.; Dorsa, Daniel M. (1998-09-01)."Transcriptional Effects of Estrogen on Neuronal Neurotensin Gene Expression Involve cAMP/Protein Kinase A-Dependent Signaling Mechanisms".Journal of Neuroscience.18(17): 6672–6680.doi:10.1523/JNEUROSCI.18-17-06672.1998.ISSN0270-6474.PMC6792960.PMID9712639.
- ^Smith, Matthew J.; Wise, Phyllis M. (2001-07-01)."Neurotensin Gene Expression Increases during Proestrus in the Rostral Medial Preoptic Nucleus: Potential for Direct Communication with Gonadotropin-Releasing Hormone Neurons*".Endocrinology.142(7): 3006–3013.doi:10.1210/endo.142.7.8256.ISSN0013-7227.PMID11416022.
- ^Driessen, Terri M.; Zhao, Changjiu; Whittlinger, Anna; Williams, Horecia; Gammie, Stephen C. (2014-01-08)."Endogenous CNS Expression of Neurotensin and Neurotensin Receptors Is Altered during the Postpartum Period in Outbred Mice".PLOS ONE.9(1): e83098.Bibcode:2014PLoSO...983098D.doi:10.1371/journal.pone.0083098.ISSN1932-6203.PMC3885409.PMID24416154.
- ^McHenry, Jenna A.; Otis, James M.; Rossi, Mark A.; Robinson, J. Elliott; Kosyk, Oksana; Miller, Noah W.; McElligott, Zoe A.; Budygin, Evgeny A.; Rubinow, David R.; Stuber, Garret D. (March 2017)."Hormonal gain control of a medial preoptic area social reward circuit".Nature Neuroscience.20(3): 449–458.doi:10.1038/nn.4487.ISSN1546-1726.PMC5735833.PMID28135243.
- ^Merullo, Devin P.; Asogwa, Chinweike N.; Sanchez-Valpuesta, Miguel; Hayase, Shin; Pattnaik, Bikash R.; Wada, Kazuhiro; Riters, Lauren V. (2018)."Neurotensin and neurotensin receptor 1 mRNA expression in song-control regions changes during development in male zebra finches".Developmental Neurobiology.78(7): 671–686.doi:10.1002/dneu.22589.ISSN1932-846X.PMC6023781.PMID29569407.
- ^Kim, Ji Tae; Weiss, Heidi L.; Evers, B. Mark (2017-06-01)."Diverse expression patterns and tumorigenic role of neurotensin signaling components in colorectal cancer cells".International Journal of Oncology.50(6): 2200–2206.doi:10.3892/ijo.2017.3990.ISSN1019-6439.PMC5435327.PMID28498396.
- ^Rodríguez, Yurena; Almeida, Teresa A.; Valladares, Francisco; Báez, Delia; Montes de Oca, Francisco; García, Candelaria; Dorta, Idaira; Hernández, Mariano; Reyes, Ricardo; Bello, Aixa R. (2010-10-01)."Neurotensin and Neurotensin Receptor 1 Expression in Human Myometrium and Uterine Leiomyomas1".Biology of Reproduction.83(4): 641–647.doi:10.1095/biolreprod.110.084962.ISSN0006-3363.PMID20592307.
External links[edit]
- Neurotensinat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- Saplakoglu, Yasemin (2022-09-07)."A Good Memory or a Bad One? One Brain Molecule Decides".Quanta Magazine.