Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats.
Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in enteroendocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.
Sequence and biosynthesis
Neurotensin shares significant sequence similarity in its 6 C-terminal amino acid residues with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role. The neurotensin/neuromedin N precursor can also be processed to produce large 125-138 amino acid peptides with the neurotensin or neuromedin N sequence at 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-lasting activators in 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. Neurotensin is synthesized as part of a 169-170 amino acid precursor protein that also contains the related neuropeptide neuromedin N. The peptide coding domains are located in tandem near the carboxyl terminal end of the precursor and are bounded and separated by paired basic amino acid (lysine-arginine) processing sites.
Neurotensin is a potent mitogen for colorectal cancer.
Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic. 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. These mice exhibit modest defects in prepulse inhibition (PPI) of the startle 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 antipsychotic haloperidol and the newer atypical antipsychotic quetiapine were 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 not clozapine administration 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.
Neurotensin is an endogenous neuropeptide involved in thermoregulation that can induce hypothermia and neuroprotection in experimental models of cerebral ischemia.
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Carraway R, Leeman SE (1973). "The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami". J. Biol. Chem. 248 (19): 6854–61. PMID 4745447.
- ↑ 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. PMID 11811984.
- ↑ Carraway R, Leeman SE (1975). "The amino acid sequence of a hypothalamic peptide, neurotensin". J. Biol. Chem. 250 (5): 1907–11. PMID 1167549.
- ↑ 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. doi:10.1073/pnas.84.10.3516. PMC 304902. PMID 3472221.
- ↑ 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. PMID 2832414.
- ↑ 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. PMC 2613866. PMID 17000667.
- ↑ 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. PMID 15987829.
- ↑ 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. doi:10.1073/pnas.141042198. PMC 35465. PMID 11427716.
- ↑ 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. PMID 15090966.