Peptides (v.27, #10)

Introduction by Robert E Carraway; Charalabos Pothoulakis; Susan Leeman (2361-2363).

Brain neurotensin, psychostimulants, and stress – emphasis on neuroanatomical substrates by Stefanie Geisler; Anne Bérod; Daniel S. Zahm; William Rostène (2364-2384).
Neurotensin (NT) is a peptide that is widely distributed throughout the brain. NT is involved in locomotion, reward, stress and pain modulation, and in the pathophysiology of drug addiction and depression. In its first part this review brings together relevant literature about the neuroanatomy of NT and its receptors. The second part focuses on functional–anatomical interactions between NT, the mesotelencephalic dopamine system and structures targeted by dopaminergic projections. Finally, recent data about the actions of NT in processes underlying behavioral sensitization to psychostimulant drugs and the involvement of NT in the regulation of the hypothalamo–pituitary–adrenal gland axis are considered.
Keywords: Neuroanatomy; Receptors; Dopamine; Amphetamine; Hypothalamo–pituitary–adrenal axis; Corticotrophin-releasing hormone;

Neurotensin: Role in psychiatric and neurological diseases by Ricardo Cáceda; Becky Kinkead; Charles B. Nemeroff (2385-2404).
Neurotensin (NT), an endogenous brain–gut peptide, has a close anatomical and functional relationship with the mesocorticolimbic and neostriatal dopamine system. Dysregulation of NT neurotransmission in this system has been hypothesized to be involved in the pathogenesis of schizophrenia. Additionally, NT containing circuits have been demonstrated to mediate some of the mechanisms of action of antipsychotic drugs, as well as the rewarding and/or sensitizing properties of drugs of abuse. NT receptors have been suggested to be novel targets for the treatment of psychoses or drug addiction.
Keywords: Neurotensin; Dopamine; Schizophrenia; Antipsychotic drugs; Drugs of abuse; Parkinson's disease;

Neurotensin and pain modulation by Paul R. Dobner (2405-2414).
Neurotensin (NT) can produce a profound analgesia or enhance pain responses, depending on the circumstances. Recent evidence suggests that this may be due to a dose-dependent recruitment of distinct populations of pain modulatory neurons. NT knockout mice display defects in both basal nociceptive responses and stress-induced analgesia. Stress-induced antinociception is absent in these mice and instead stress induces a hyperalgesic response, suggesting that NT plays a key role in the stress-induced suppression of pain. Cold water swim stress results in increased NT mRNA expression in hypothalamic regions known to project to periaqueductal gray, a key region involved in pain modulation. Thus, stress-induced increases in NT signaling in pain modulatory regions may be responsible for the transition from pain facilitation to analgesia. This review focuses on recent advances that have provided insights into the role of NT in pain modulation.
Keywords: Neurotensin; Antinociception; Analgesia;

The present study evaluated whether neurotensin (NT) binding sites were altered in the aged rat brain and if these alterations were related to the cognitive status of the animal. Aged (24–25 months old) Long–Evans rats were behaviorally screened using the Morris water maze task and were classified as either aged, cognitively impaired (AI) or cognitively unimpaired (AU) based on their relative performances in the task compared to young control (Y) animals. Decreases in specific [125I]NT binding were observed in the hippocampal formation, namely the dentate gyrus (DG), as well as in the septum and hypothalamus. Both aged groups also showed significant reductions in specific [125I]NT binding levels compared to the Y animals in the hippocampal CA3 sub-field, with the AI animals exhibiting the lowest levels. In the Substantia Nigra Zona Compacta (SNc) and the ventral tegmental area (VTA), specific [125I]NT binding was decreased as a function of age while binding in the paraventricular nucleus of the hypothalamus (PVNh) was decreased as a function of age and cognitive status. These alterations in the level of specific [125I] NT binding in the aged animals suggest decreases in NT receptor signaling as a function of age and potential involvement of NT-ergic systems in the etiology of age-related cognitive deficits.
Keywords: Spatial memory; Acetylcholine; Hypothalamic-pituitary-adrenal axis; Hippocampus;

Neurotensin (NT) is a brain-gut tridecapeptide that functions as a neurotransmitter/neuromodulator in the central nervous system (CNS) and as an endocrine agent in the periphery. NT has numerous physiologic effects on multiple organs. This review will focus on the effects of NT as a trophic factor for normal and neoplastic tissues. In this regard, NT may act as an endocrine agent or, in some instances, in a paracrine and/or autocrine fashion. These effects appear to be mediated predominantly through the G protein-coupled high-affinity NT receptor. However, some of the trophic effects may also be through the other two receptor subtypes, particularly the NT receptor type 3, which belongs to a recently identified family of sorting receptors. The signaling pathways mediating the effects of NT are multiple but most appear to activate the ERK signaling pathway, which then activates downstream transcription factors, ultimately leading to proliferation. NT may be a useful agent to enhance the growth of normal tissues such as the small bowel mucosa during periods of gut disuse or disease and, finally, the selective targeting of NT receptor subtypes on certain cancers may offer a novel strategy in the armamentarium of cancer chemotherapeutics.
Keywords: Neurotensin; Neoplastic tissue; Neurotensin receptor; ERK; Proliferation;

It is well established that interactions of neuropeptides with several cell types at various parts of the intestine are critically involved in intestinal pathophysiology. Among them, neurotensin has been identified as an important mediator in the development and progress of several gastrointestinal functions and disease conditions, exerting its effects by interacting with specific receptors that exert direct and indirect effects on nerves, epithelial cells, and cells of the immune and inflammatory systems. This review summarizes our recent understanding on the participation of neurotensin in the physiology and pathophysiology of the small and large intestine, and discusses various mechanisms that could be involved in these actions.
Keywords: Neurotensin; GI tract; motility; Inflammation; Signaling;

Focusing on the literature of the past 15 years, we evaluate the evidence that neurotensin and neurotensin receptors participate in cancer growth and we describe possible mechanisms. In addition, we review the progress achieved in the use of neurotensin analogs to image tumors in animals and humans. These exciting advances encourage us to pursue further research and stimulate us to consider novel ideas regarding the multiple inputs to cancer growth that neurotensin might influence.
Keywords: Neurotensin; Cell growth; Cancer; Signaling; Imaging; SR48692;

The subtype 1 neurotensin receptor (NTS1) belongs to the family of G protein coupled receptors with seven transmembrane domains and mediates most of the known effects of neurotensin. In the past years, mutagenesis studies have allowed to delineate functional regions of the receptor involved in agonist and antagonist binding, G protein coupling, sodium sensitivity of agonist binding, and agonist-induced receptor internalization. These data are reviewed and discussed in the present paper.
Keywords: NTS1; GPCR; G proteins; Agonist; Antagonist; Constitutive activity;

Functional roles of the NTS2 and NTS3 receptors by Jean Mazella; Jean-Pierre Vincent (2469-2475).
Neurotensin exerts its actions in the central nervous system and the periphery through three identified receptors. Two of them, the NTS2 and NTS3, display unusual properties either because of their complex signal transduction mechanisms (NTS2) or because of their structural composition as a non-G-protein-coupled receptor (NTS3). Here, we review the transduction mechanisms, cellular trafficking, and potential physiological roles of these two unconventional receptors.
Keywords: Neurotensin; Receptor; NTS2; NTS3/sortilin; Signaling; Expression; Regulation;

Three neurotensin (NT) receptors have been cloned to date, two of which, NTS1 and NTS2, belong to the family of seven transmembrane domain receptors coupled to G proteins (GPCRs). NTS1 and NTS2 may activate multiple signal transduction pathways, involving several G proteins. However, whereas NT acts as an agonist towards all NTS1-mediated pathways, this peptide may exert either agonist or antagonist activities, depending on the NTS2-mediated pathway in question. Studies on these receptors reinforce the concept of independence between multiple signals potentially mediated through a single GPCR, generating a wide diversity of functional responses depending on the host cell and the ligand.
Keywords: Neurotensin; Receptors; G protein;

Internalization and recycling properties of neurotensin receptors by Jean Mazella; Jean-Pierre Vincent (2488-2492).
The targeting, internalization and recycling of membrane receptors in response to extracellular ligands involve a series of molecular mechanisms which are beginning to be better understood. The receptor-dependent internalization of neurotensin has been widely investigated using endogenous or heterologous receptor expression systems. This review focuses on the general properties of neurotensin sequestration and on the characterization of the receptors involved in this process.
Keywords: Neurotensin; Receptor; NTS1; NTS2; NTS3/sortilin; Internalization; Recycling; Trafficking;

Neurotensin is a tridecapteptide acting mostly in the brain and gastrointestinal tract. NT binds two G protein coupled receptors (GPCR), NTS1 and NTS2, and a single transmembrane domain receptor, NTS3/gp95/sortilin receptor. NTS1 mediates the majority of NT action in neurons and the periphery. Like many other GPCRs, upon agonist stimulation, NTS1 is internalized, endocytosed, and the cells are desensitized. It is tacitly acknowledged that the intensity and the lasting of cellular responses to NT are dependent on free and functional NTS1 at the cell surface. Understanding how NTS1 expression is regulated at the membrane should provide a better comprehension towards its function. This review analyzes and discusses the current cellular and molecular mechanisms affecting the expression of NTS1 at the cellular membrane upon acute and chronic NT stimulation.
Keywords: Neurotensin receptor; Chronic agonist stimulation; G protein;

Internalization-dependent regulation of HT29 cell proliferation by neurotensin by Valérie Navarro; Stéphane Martin; Jean Mazella (2502-2507).
In this study, we have investigated the involvement of the internalization process induced by neurotensin (NT) on MAP kinases Erk1/2 activation, inositol phosphates (IP) accumulation and cell growth in the human colonic cancer cell line HT29. Reversible blocking of NT/neurotensin receptor (NTR) complex endocytosis by hyperosmolar sucrose totally abolished both the phosphorylation of the MAP kinases Erk1/2 and the [3H]-thymidine incorporation induced by the peptide. By contrast, NT-evoked IP formation was not affected by sucrose treatment. These results therefore indicate that NT/NTR complex endocytosis triggers MAP kinase activation and subsequently the growth of HT29 cells. This property could be useful for the development of novel anticancer treatments.
Keywords: Neurotensin; Neurotensin receptor-3; Cell growth; MAP kinases;

Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid neurotensin-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by endoproteases that belong to the recently identified family of pro-protein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Pro-NT/NN processing gives rise mainly to NT and NN in the brain, to NT and a large peptide ending with the NN sequence at its C-terminus (large NN) in the gut and to NT, large NN and a large peptide ending with the NT sequence (large NT) in the adrenals. Recent evidence indicates that PC1, PC2 and PC5-A are the pro-hormone convertases responsible for the processing patterns observed in the gut, brain and adrenals, respectively. As NT, NN, large NT and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that post-translational processing of pro-NT/NN in tissues may generate biological diversity.
Keywords: Neurotensin; Neuromedin N; Peptides; Processing; Pro-hormone convertases;

The two related peptides neurotensin (NT) and neuromedin N (NN) are efficiently inactivated by peptidases in vitro. Whereas NT is primarily degraded by a combination of three Zn metallo-endopeptidases, namely endopeptidases 24.11, 24.15 and 24.16, in all systems examined, NN is essentially inactivated by the Zn metallo-exopeptidase aminopeptidase M. In this paper we review the work that has led to the identification of the NT- and NN-degrading enzymes and to the purification and cloning of EP 24.16, a previously unidentified peptidase. We provide a brief description of the three NT-inactivating endopeptidases and of their specific and mixed inhibitors, some of them developed in the course of studying NT degradation. Finally, we review in vivo data obtained with these inhibitors that strongly support a physiological role for EP 24.11, 24.15 and 24.16 in the termination of NT-generated signals and for aminopeptidase in terminating NN action. Knowledge of the NT and NN inactivation mechanisms offers the perspective to develop metabolically stable analogs of these peptides with potential therapeutic value.
Keywords: Neurotensin; Neuromedin N; Degradation; EC.3.4.24.11; EC.3.4.25.15; EC.3.4.25.16; Aminopeptidase M;

Bioactive analogs of neurotensin: Focus on CNS effects by Mona Boules; Paul Fredrickson; Elliott Richelson (2523-2533).
Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood–brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinson's disease and addiction.
Keywords: Neurotensin; Neurotensin analogs; Neurotensin antagonists; Neurotensin receptors;