| 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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| NTS | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | NTS, NMN-125, NN, NT, NT/N, NTS1, neurotensin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:162650;MGI:1328351;HomoloGene:4506;GeneCards:NTS;OMA:NTS - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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). | |
Neurotensin is a 13amino acidneuropeptide that is implicated in the regulation ofluteinizing hormone andprolactin release and has significant interaction with thedopaminergic system. Neurotensin was first isolated from extracts ofbovinehypothalamus based on its ability to cause a visiblevasodilation in the exposedcutaneous regions of anesthetized rats.[5]
Neurotensin is distributed throughout the central nervous system, with highest levels in thehypothalamus,amygdala andnucleus accumbens. It induces a variety of effects, includinganalgesia,hypothermia, andincreased locomotor activity. It is also involved inregulation of dopamine pathways. In the periphery, neurotensin is found inenteroendocrine cells of the small intestine, where it leads topancreatic andbiliarysecretion, reducedgastric acid secretion, andsmooth muscle contraction.[6]
Neurotensin shares significant sequence similarity in its 6C-terminalamino acids with several other neuropeptides, includingneuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the fullbiological activity, theN-terminal portion having a modulatory role. The neurotensin/neuromedin Nprecursor can also be processed to produce large 125–138amino acidpeptides with the neurotensin or neuromedin Nsequence 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-lastingactivators 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.[7] Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptideneuromedin N.[8][9] The peptide coding domains are located in tandem near thecarboxyl terminal end of theprecursor and are bounded and separated by paired basicamino acid (lysine-arginine) processing sites.
Neurotensin is involved in a variety of central and peripheral processes. In the brain, it plays a role in modulating hormone activity, social behavior, and learning. For example, neurotensin-expressing neurons in the medial preoptic area (mPOA) of mice project to theventral tegmental area (VTA), where they contribute to social reward processing and the encoding of odor cues, suggesting a role in both hormonal signaling and reward circuits.[10]
Neurotensin also appears to influence learning processes. In male zebra finches, expression of neurotensin and its receptor genes varies during song development. Both neurotensin and neurotensin receptor mRNA levels decrease during the transition from the sensory to sensorimotor phases of development, implicating neurotensin in the onset of sensorimotor learning. Later in development, neurotensin and neurotensin receptor 1 (Ntsr1) show complementary expression patterns in song-related brain regions, suggesting dynamic modulation of neural responses.[11]
In peripheral tissues, neurotensin is predominantly expressed in the gastrointestinal tract, where it participates in digestion and local signaling. Its aberrant expression has also been associated with tumorigenesis.
Neurotensin gene expression is modulated by hormonal and intracellular signaling pathways. In human SK-N-SHneuroblastoma cell cultures and in mice,estrogen has been shown to enhance neurotensin transcription through the activation ofcyclic AMP (cAMP) signaling pathways. Estrogen increases cAMP levels and promotesphosphorylation of cAMP response element-binding protein (CREB), a precursor event to neurotensin gene activation. This effect is absent inknockout mice lacking the RIIβ subunit ofprotein kinase A, highlighting the importance of the cAMP/PKA signaling axis in neurotensin regulation.[12]In female rats, neurotensin mRNA expression peaks in the mPOA during the proestrus phase of theestrous cycle, suggesting regulation by ovarian hormones.[13]Postpartum hormonal states also influence neurotensin and neurotensin receptor expression. In postpartum female mice, neurotensin levels were increased in the paraventricular nucleus (PVN) of the hypothalamus despite reduced Ntsr1 mRNA. Both neurotensin mRNA and peptide levels were elevated in the mPOA, changes that were absent in virgin controls. These patterns are consistent with a regulatory role in maternal behaviors.[14]
Aberrant neurotensin signaling has been implicated in several pathological conditions, particularly in cancer. In colorectal cancer cells, expression of neurotensin receptor genes (NTSR1 and NTSR2) is regulated by promoterDNA methylation. Downregulation of NTSR1 through RNA interference or pharmacological antagonism results in reduced cell proliferation and migration, indicating a tumor-promoting role for this pathway.[15]Neurotensin expression has also been observed inleiomyomas, or fibroid tumors, of the uterus. Both neurotensin and NTSR1 levels are elevated in fibroid tissues compared to normal uterine tissue, suggesting a role in the pathophysiology of uterine smooth muscle proliferation.[16]
Neurotensin is a potentmitogen forcolorectal cancer.[17]
Neurotensin has been implicated in the modulation ofdopamine signaling, 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.[18] 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 antipsychotichaloperidol and the newer atypical antipsychoticquetiapine 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 notclozapine 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.[19]
Neurotensin is an endogenous neuropeptide involved inthermoregulation that can inducehypothermia andneuroprotection in experimental models ofcerebral ischemia.[20]
