Neurotensin

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Neurotensin (NT) can activate the G protein-coupled receptor, the neurotensin receptor 1 (NTR1). NT, a 13-amino acid neuropeptide, expressed in the central nervous system, and the intestine, including ileum3 and colon.

Neurotensin receptor 1 (NTR1) is a G protein-coupled receptor (neurotensin, NT) with high affinity.

In vitro: Due to NT/NTR1 signaling potentiates expression of miR-133α, the mechanism of NT-regulated miR-133α expression and examining the role of miR-133α in intracellular NTR1 trafficking in human NCM460 colonocytes are very important. The negative transcription regulator (zinc finger E-box binding homeobox 1) is involved in NT-induced miR-133α upregulation. A binding target of miR-133α (silencing of miR-133α or overexpression of aftiphilin (AFTPH)) lowered NTR1 trafficking to plasma membrane in human colonocytes without affecting NTR1 internalization. AFTPH to early endosomes and the trans-Golgi network (TGN) were localized in unstimulated human colonic epithelial cells. NTR1 localization was reduced by AFTPH overexpression in early endosomes. At the same time, it also increased expression of proteins related to endosomes and the TGN trafficking pathway. NTR1 expression was increased by AFTPH overexpression and de-acidification of intracellular vesicles. These results suggest a novel mechanism of GPCR trafficking in human colonic epithelial cells accounts for why a microRNA, miR-133α regulates NTR1 trafficking through its downstream target AFTPH.

In vivo: So far, no study in vivo has been conducted.

Clinical trial: So far, no clinical study has been conducted.

Reference:
[1].  Law IK, Jensen D, Bunnett NW, Pothoulakis C. Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep. 2016 Feb 23;6:22195.

Use of Molecular Modeling to Design Selective NTS2 Neurotensin Analogues.[Pubmed:28368584]

J Med Chem. 2017 Apr 27;60(8):3303-3313.

Neurotensin exerts potent analgesia by acting at both NTS1 and NTS2 receptors, whereas NTS1 activation also results in other physiological effects such as hypotension and hypothermia. Here, we used molecular modeling approach to design highly selective NTS2 ligands by investigating the docking of novel NT[8-13] compounds at both NTS1 and NTS2 sites. Molecular dynamics simulations revealed an interaction of the Tyr(11) residue of NT[8-13] with an acidic residue (Glu(179)) located in the ECL2 of hNTS2 or with a basic residue (Arg(212)) at the same position in hNTS1. The importance of the residue at position 11 for NTS1/NTS2 selectivity was further demonstrated by the design of new NT analogues bearing basic (Lys, Orn) or acid (Asp or Glu) function. As predicted by the molecular dynamics simulations, binding of NT[8-13] analogues harboring a Lys(11) exhibited higher affinity toward the hNTS1-R212E mutant receptor, in which Arg212 was substituted by the negatively charged Glu residue.

Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance.[Pubmed:28323938]

Endocrinology. 2017 May 1;158(5):1271-1288.

The hormones ghrelin and leptin act via the lateral hypothalamic area (LHA) to modify energy balance, but the underlying neural mechanisms remain unclear. We investigated how leptin and ghrelin engage LHA neurons to modify energy balance behaviors and whether there is any crosstalk between leptin and ghrelin-responsive circuits. We demonstrate that ghrelin activates LHA neurons expressing hypocretin/orexin (OX) to increase food intake. Leptin mediates anorectic actions via separate neurons expressing the long form of the leptin receptor (LepRb), many of which coexpress the neuropeptide Neurotensin (Nts); we refer to these as NtsLepRb neurons. Because NtsLepRb neurons inhibit OX neurons, we hypothesized that disruption of the NtsLepRb neuronal circuit would impair both NtsLepRb and OX neurons from responding to their respective hormonal cues, thus compromising adaptive energy balance. Indeed, mice with developmental deletion of LepRb specifically from NtsLepRb neurons exhibit blunted adaptive responses to leptin and ghrelin that discoordinate the mesolimbic dopamine system and ingestive and locomotor behaviors, leading to weight gain. Collectively, these data reveal a crucial role for LepRb in the proper formation of LHA circuits, and that NtsLepRb neurons are important neuronal hubs within the LHA for hormone-mediated control of ingestive and locomotor behaviors.

A Review of the Role of Neurotensin and Its Receptors in Colorectal Cancer.[Pubmed:28316623]

Gastroenterol Res Pract. 2017;2017:6456257.

Neurotensin (NTS) is a physiologically occurring hormone which affects the function of the gastrointestinal (GI) tract. In recent years, NTS, acting through its cellular receptors (NTSR), has been implicated in the carcinogenesis of several cancers. In colorectal cancer (CRC), a significant body of evidence, from in vitro and in vivo studies, is available which elucidates the molecular biology of NTS/NTSR signalling and the resultant growth of CRC cells. There is growing clinical data from human studies which corroborate the role NTS/NTSR plays in the development of human CRC. Furthermore, blockade and modulation of the NTS/NTSR signalling pathways appears to reduce CRC growth in cell cultures and animal studies. Lastly, NTS/NTSR also shows potential of being utilised as a diagnostic biomarker for cancers as well as targets for functional imaging. We summarise the existing evidence and understanding of the role of NTS and its receptors in CRC.

The signaling signature of the neurotensin type 1 receptor with endogenous ligands.[Pubmed:28341345]

Eur J Pharmacol. 2017 Jun 15;805:1-13.

The human Neurotensin 1 receptor (hNTS1) is a G protein-coupled receptor involved in many physiological functions, including analgesia, hypothermia, and hypotension. To gain a better understanding of which signaling pathways or combination of pathways are linked to NTS1 activation and function, we investigated the ability of activated hNTS1, which was stably expressed by CHO-K1 cells, to directly engage G proteins, activate second messenger cascades and recruit beta-arrestins. Using BRET-based biosensors, we found that Neurotensin (NT), NT(8-13) and neuromedin N (NN) activated the Galphaq-, Galphai1-, GalphaoA-, and Galpha13-protein signaling pathways as well as the recruitment of beta-arrestins 1 and 2. Using pharmacological inhibitors, we further demonstrated that all three ligands stimulated the production of inositol phosphate and modulation of cAMP accumulation along with ERK1/2 activation. Interestingly, despite the functional coupling to Galphai1 and GalphaoA, NT was found to produce higher levels of cAMP in the presence of pertussis toxin, supporting that hNTS1 activation leads to cAMP accumulation in a Galphas-dependent manner. Additionally, we demonstrated that the full activation of ERK1/2 required signaling through both a PTX-sensitive Gi/o-c-Src signaling pathway and PLCbeta-DAG-PKC-Raf-1-dependent pathway downstream of Gq. Finally, the whole-cell integrated signatures monitored by the cell-based surface plasmon resonance and changes in the electrical impedance of a confluent cell monolayer led to identical phenotypic responses between the three ligands. The characterization of the hNTS1-mediated cellular signaling network will be helpful to accelerate the validation of potential NTS1 biased ligands with an improved therapeutic/adverse effect profile.

Neurotensin and dopamine interactions.[Pubmed:11734615]

Pharmacol Rev. 2001 Dec;53(4):453-86.

Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter Neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implications-always with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.

Neurotensin: peptide for the next millennium.[Pubmed:11033059]

Regul Pept. 2000 Sep 25;93(1-3):125-36.

Neurotensin is an endogenous tridecapeptide neurotransmitter (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH) that was discovered by Carraway and Leeman in bovine hypothalami in the early 1970s. Since then this peptide has been the subject of a multitude of articles detailing discoveries related to its activity, receptors, localization, synthesis, and interactions with other systems. This review article does not intend to summarize again all the history of this fascinating peptide and its receptors, since this has been done quite well by others. The reader will be directed to these other reviews, where appropriate. Instead, this review attempts to provide a summary of current knowledge about Neurotensin, why it is an important peptide to study, and where the field is heading. Special emphasis is placed on the behavioral studies, particularly with reference to agonists, antagonists, and antisense studies, as well as, the interaction of Neurotensin with other neurotransmitters.

Neurotensin and neurotensin receptors.[Pubmed:10390649]

Trends Pharmacol Sci. 1999 Jul;20(7):302-9.

Neurotensin is a brain and gastrointestinal peptide that fulfils many central and peripheral functions through its interaction with specific receptors. Three subtypes of Neurotensin receptors have been cloned. Two of them belong to the family of G protein-coupled receptors, whereas the third one is an entirely new type of neuropeptide receptor and is identical to gp95/sortilin, a 100 kDa-protein with a single transmembrane domain. In this review, the present knowledge regarding the molecular and pharmacological properties of the three cloned Neurotensin receptors is summarized and the relationship between these receptors and the known pharmacological effects of Neurotensin is discussed.

Neurotensin, a gut tridecapeptide, acts as a potent cellular mitogen for various colorectal and pancreatic cancers which possess high-affinity neurotensin receptors (NTR).

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