Neurotensin

Sequence and biosynthesis

Neurotensin shares significant sequence similarity in its 6 C-terminal amino acids 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 or 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.

Function

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 the ventral 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.

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.

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.

Regulation

Neurotensin gene expression is modulated by hormonal and intracellular signaling pathways. In human SK-N-SH neuroblastoma cell cultures and in mice, estrogen has been shown to enhance neurotensin transcription through the activation of cyclic AMP (cAMP) signaling pathways. Estrogen increases cAMP levels and promotes phosphorylation of cAMP response element-binding protein (CREB), a precursor event to neurotensin gene activation. This effect is absent in knockout mice lacking the RIIβ subunit of protein kinase A, highlighting the importance of the cAMP/PKA signaling axis in neurotensin regulation. In female rats, neurotensin mRNA expression peaks in the mPOA during the proestrus phase of the estrous cycle, suggesting regulation by ovarian hormones. 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.

Clinical significance

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 promoter DNA 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. Neurotensin expression has also been observed in leiomyomas, 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.

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.

References

References

1. (Oct 1973). "The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami". Journal of Biological Chemistry.
2. (February 2002). "Production of recombinant large proneurotensin/neuromedin N-derived peptides and characterization of their binding and biological activity". Biochemical and Biophysical Research Communications.
3. (Mar 1975). "The amino acid sequence of a hypothalamic peptide, neurotensin". Journal of Biological Chemistry.
4. (May 1987). "Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor". Proceedings of the National Academy of Sciences of the United States of America.
5. (Apr 1988). "The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences". Journal of Biological Chemistry.
6. (March 2017). "Hormonal gain control of a medial preoptic area social reward circuit". Nature Neuroscience.
7. (2018). "Neurotensin and neurotensin receptor 1 mRNA expression in song-control regions changes during development in male zebra finches". Developmental Neurobiology.
8. (1998-09-01). "Transcriptional Effects of Estrogen on Neuronal Neurotensin Gene Expression Involve cAMP/Protein Kinase A-Dependent Signaling Mechanisms". The Journal of Neuroscience.
9. (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.
10. (2014-01-08). "Endogenous CNS Expression of Neurotensin and Neurotensin Receptors Is Altered during the Postpartum Period in Outbred Mice". PLOS ONE.
11. (2017-06-01). "Diverse expression patterns and tumorigenic role of neurotensin signaling components in colorectal cancer cells". International Journal of Oncology.
12. (2010-10-01). "Neurotensin and Neurotensin Receptor 1 Expression in Human Myometrium and Uterine Leiomyomas1". Biology of Reproduction.
13. (September 2006). "Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells". Clinical Cancer Research.
14. (Oct 2005). "Neurotensin-deficient mice have deficits in prepulse inhibition: restoration by clozapine but no haloperidol, olanzapine, or quetiapine". The Journal of Pharmacology and Experimental Therapeutics.
15. (Jul 2001). "Neurotensin-deficient mice show altered responses to antipsychotic drugs". Proceedings of the National Academy of Sciences of the United States of America.
16. (March 2004). "Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia". Critical Care Medicine.