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.[6]
Sequence and biosynthesis
Neurotensin shares significant sequence similarity in its 6 C-terminalamino 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 acidpeptides 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.[7] Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptide neuromedin N.[8][9] 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 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.[11] 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.[12]
Neurotensin gene expression has been shown to be modulated by estrogen in both human SK-N-SH neuroblastoma cell cultures as well as in mice through interactions with cyclic AMP (cAMP) signaling. Specifically, estrogen increased cAMP activity and cAMP response element-binding protein phosphorylation in neuroblastoma cells prior to the induction of neurotensin gene transcription. Additionally, neurotensin gene transcription was blocked in knock-out mice lacking the RIIβ subunit of the protein kinase A holoenzyme. These findings may indicate mechanisms of cross-talk signaling in brain hormone activity and expression of hormone-related genes.[14] Other sex hormone-related changes in neurotensin expression have been associated with activity in the preoptic area. In female rats, neurotensin expression was shown to be at its highest in the medial preoptic area (mPOA) during the proestrus phase of the estrous cycle.[15]
Altered expression of neurotensin genes as well as neurotensin receptor genes have been exhibited in postpartum female mice. While neurotensin receptor 1 (Ntsr1) mRNA in the paraventricular 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.[16]
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 the ventral 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.[17]
Neurotensin has also been implicated in learning processes. A study examining song development in male zebra finches showed variations in neurotensin and neurotensin receptor gene 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.[18]
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 promoter methylation has 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 NTSR1 antagonist inhibited colorectal cancer cell proliferation and migration.[19]Leiomyomas or fibroid tumors in uterine tissue have also been associated with higher expression of neurotensin and NTSR1.[20]
Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it.
Substance P (SP) is an undecapeptide member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.
Gastrin-releasing peptide, also known as GRP, is a neuropeptide, a regulatory molecule that has been implicated in a number of physiological and pathophysiological processes. Most notably, GRP stimulates the release of gastrin from the G cells of the stomach.
Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gallbladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.
Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).
Neuropeptide Y receptors are a family of receptors belonging to class A G-protein coupled receptors and they are activated by the closely related peptide hormones neuropeptide Y, peptide YY and pancreatic polypeptide. These receptors are involved in the control of a diverse set of behavioral processes including appetite, circadian rhythm, and anxiety.
Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.
Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.
Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.
Neuromedin N is a neuropeptide derived from the same precursor polypeptide as neurotensin, and with similar but subtly distinct expression and effects.
The neuromedin U receptors are two G-protein coupled receptors which bind the neuropeptide hormones neuromedin U and neuromedin S. There are two subtypes of the neuromedin U receptor, each encoded by a separate gene.
Neuromedin U is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.
The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.
Neurotensin receptor type 2 is a protein that in humans is encoded by the NTSR2 gene.
Neurotensin receptor type 1 is a protein that in humans is encoded by the NTSR1 gene. For a crystal structure of NTS1, see pdb code 4GRV. High-resolution crystal structures have been determined in complex with the peptide full agonist NT8-13, non-peptide full agonist SRI-9829, partial agonist RTI-3a, antagonists / inverse agonists SR-48692 and SR-142948, as well as in the ligand-free state.
Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene. It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type. Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro, and metabolism of neurotensin is the most important role of neurolysin in vivo. Neurolysin has also been implicated in pain control, blood pressure regulation, sepsis, reproduction, cancer biology pathogenesis of stroke, and glucose metabolism.
Neuromedin S is a 36-amino acid neuropeptide found in the brain of humans and other mammals. It is produced in the suprachiasmatic nucleus of the hypothalamus and is related to neuromedin U. It is thought to be involved in regulation of circadian rhythm and also has appetite suppressant effects, as well as regulating the release of several other peptide hormones including vasopressin, luteinizing hormone, and oxytocin.
↑ 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.
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