Neurotensin

Neurotensin is a tridecapeptide neurotransmitter implicated in the regulation of a variety of anterior pituitary hormones including prolactin, growth hormone, thyrotropin, adrenocorticotropin and the gonadotropins (for review, see Aronin et al., 1986 Rostene 

Radioligand binding experiments reveal both high and low affinity binding sites for neurotensin in the mammalian brain (Mazella et al., 1983 Kitabgi et al., 1985 Vincent, 

Whether neurotensin acts directly at NTRi receptors on TIDA neurons is not clear. The presence of dense neurotensin binding sites located within the mediobasal hypothalamus (Goedert et al., 1985 Meister et al., 1989) and the observation that single unit activity of approximately 70% of all DM-ARC neurons is stimulated by neurotensin in vitro suggest a localized action on (or near) TIDA neurons (Lin and Pan, 1993). Moreover, the presence of synaptic connections between neurotensin-IR and TH-IR neurons in the DM-ARC is consistent with a direct action of neurotensin on TIDA neurons (Marcos et al., 1996a). On the other hand, TIDA neurons do not normally express appreciable amounts of neurotensin receptor mRNA like mesotelencephalic DA neurons 

There have been several studies characterizing the stimulatory effects of neurotensin on PHDA neurons terminating in the intermediate lobe of the posterior pituitary. Central (icv) administration of neurotensin increases the activity of PHDA neurons and this causes a concomitant decrease in concentration of aMSH in plasma (Pan et al., 1992). Neurotensin stimulates DA release in vitro from explants containing PHDA neurons, but not from isolated neurointermediate lobes, which is consistent with a hypothalamic site of action of neurotensin in stimulating the activity of PHDA neurons (Davis and Kilts 1987a,b). Neurotensin causes a sustained excitation of DA release from PHDA neurons with little or no tolerance as compared with short-lived transient responses of mesolimbic DA neurons to neurotensin (Davis and Kilts, 1987b). 

Little information is available regarding the effects of neurotensin on diencephalic DA neurons comprising the IHDA or PeVDA systems. Central administration of neurotensin increases DOPAC concentrations in whole hypothalamus (Widerlov et al., 1982 Minano et al., 1988), but the contribution of activated TIDA neurons to tissue DOPAC levels 

Neurotensin [NT pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu (pGlu = pyroglutamic add)] is a neuromodulator that stimulates the formation of intracellular cyclic guanosine monophosphate (c-GMP) and the turnover of phosphatidylinositold o Neurotensin receptor antagonists are of interest, in part, because of their potential as antipsychotic agents. 

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Neurotensin. This hormone has been isolated and characterized from acid—acetone extracts of bovine hypothalamus (118) on the basis of its hypotensive activity. Immunoreactive neurotensin is present in mammalian gut and is distributed throughout the central nervous system its highest concentration is in the hypothalamus and in the substantia gelatinosa of the spinal cord (119). Its overall brain distribution is not unlike that of enkephalin ( ) ... 

Biologica.1 Activities a.ndAna.logues, The many pharmacological actions of neurotensin include hypotension, increased vascular permeabihty, hyperglycemia, increased intestinal motility, and inhibition of gastric acid secretion (120). In the brain, it produces analgesia at remarkably low doses (121). 

The smallest sequence possessing most of the neurotensin spectmm of activities and its high potency is the hexapeptide C-terminus (1). [D-Trp ]-Neurotensin acts like a neurotensin antagonist in perfused heart preparations, but acts like a full agonist in guinea pig atria and rat stomach strips (122). 

Neurotensin. Neurotensia [39379-15-2] (NT),j )-Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH, is a tridecapeptide that is cleaved from the ribosomaHy synthesized precursor, proneurotensia. NT is distributed through the peripheral and central nervous systems as well as ia certain other cell types (3,67). NT is colocalized with catecholamines ia some neurons. 

A six aminoacid neurotensin-like peptides synthesized in the same propeptide precursor as neurotensin. 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

Neurotensin/Neuromedin N. Table 1 Structures and and potential therapeutical uses of NT receptor ligands... 

Neurotensin/Neuromedin N. Table 2 NTS1 and NTS2 signaling properties... 

Vincent JP, Mazella J, Kitabgi P (1999) Neurotensin and neurotensin receptors. Trends Pharmacol Sci 20 302-309... 

Kitabgi P (2002) Targeting neurotensin receptors with agonists and antagonists for therapeutic purposes. Curr Opin Drug Discov Devel 5 764—776... 

Evers BM (2006) Neurotensin and growth of normal and neoplastic tissues. Peptides 27 2424—2433... 

Caceda R, Kinkead B, Nemeroff CB (2006) Neurotensin role in psychiatric and neurological diseases. Peptides 27 2385-2404... 

Sarret P, Kitabgi P (2007) Neurotensin and receptors. The New Encyclopedia of Neuroscience (Lany squire et al., eds) in press... 

The versatility of the reagent system in the assay of small peptides is nicely illustrated in Figures 3 through 5. Neurotensin, a polypeptide composed of 13 amino acids, and three fragments from partial hydrolysis were derivatized with NDA/CN and separated by... 

Figure 3. Chromatogram of neurotensin-CBI (NTS) and neuro-tensin-fragment-CBI products (Wong, 0. S., unpublished results).

D. J., Douglas C. L, Boules M., Stewart J.A., Zhao L., Lacy B., Cusack B., Fauq A., Richelson E. Peptide nucleic acids targeted to the neurotensin receptor and administered i.p. cross the blood-brain barrier and specifically reduce gene expression. Proc. Natl Acad. Sci. USA 1999 96 7053-7058. 

Neurotensin is a peptide with well-established digestive functions which is also found in CNS neurons. There are two receptors (1 and 2) and a paucity of agonists apart from... 

It has been known for some time that the Cl -conductance of epithelial cells can, in addition to its regulation via cAMP, be enhanced by increases in cytosolic Ca " (cf. Fig. 3). This has been shown with Ca -ionophores [120,121] or with hormones increasing cytosolic Ca such as carbachol, neurotensin, ATP, etc. [50,103,104]. Usually these agonists have dual effects. They increase the Cl - as well as the K" -conductance [104]. Stubs et al. [122] have shown that CF cells still increase their Cl -conductance in response to ATP. Another mechanism of Cl -channel activation has been described in whole-cell patches of colonic carcinoma and RE cells [123,124] when the cells are exposed to hypotonic media they swell and increase their Cl -conductance. This is a rather general phenomenon which is present in a lot of cells [11]. In their effort to reduce cell volume in hypotonic media (regulatory... 

NPY Neuropeptide Y NRS Normal rabbit serum NSAID Non-steroidal antiinflammatory drug NSE Nerve-specific enolase NT Neurotensin N terminus Amino terminus of peptide... 

QUESTION Did you mention that 6-hydroxydopamine blocks or elevates neurotensin levels ... 

ANSWER Yes, 6-hydroxydopamine by itself elevates neurotensin levels. When you combine it with methamphetamine, you do not get any additivity. It is just a 6-hydroxydopamine action. It is a bit complicated to interpret, but it appears that it is still the nigral striatal dopamine pathway that is mediating the methamphetamine effect. 

RESPONSE Right. And we have asked ourselves the question because of the issue of coexistence, not only with substance P but with neurotensin and probably dynorphin. Is this the reason these things are changing Because if they are coexisting with dopamine projections and there is some alteration in dopamine, then maybe there is an intraneuronal action that results in the peptide changes. 

Letter A.A. Merchant, K. Gibb, J.W. and Hanson, G.R. Effect of meth-amphetamine on neurotensin eoneentrations in rat brain regions. 

Nemeroff C. The interaetion of neurotensin with dopaminergic pathways in the central nervous system Basie neurobiology and implications for the pathogenesis and treatment of schiiphrenia. Psychoneuroendocrinology ll(l) 15-37, 1986. 

Quirion, R. Chiueh. C. Everist, H. and Pert, A. Comparative loealization of neurotensin receptors on nigrostriatal and mesolimbic dopaminergie terminals. Brain Res 327 385-389, 1985. 

Skoog, K. Cain, S. and Nemeroff, C. Centrally administered neurotensin suppresses locomotor hyperactivity induced by d-amphetamine but not by scopolamine or caffeine. Neuropharmacology 25(7) 777-782, 1986. 

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