Neurotensin receptor–1 and –3 complex modulates the cellular signaling of neurotensin in the HT29 cell line

Martin, Stéphane; Navarro, Valérie; Vincent, Jean Pierre; Mazella, Jean

doi:10.1053/gast.2002.36000

Cited by 109 publications

(90 citation statements)

References 38 publications

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“…For instance, it was recently demonstrated that interaction between NTS1 and NTS3 decreased the potency of NT to produce InsP and also altered MAPK activation [46]. Most of the partners of NTS1, which could alter either its interaction with the G proteins or the functional consequences of these interactions, are still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…However, NTS2 also interacts with G-proteins, at least in some systems, and its striking differences with NTS1 at both molecular and functional levels, among which the finding that NT may behave as a NTS2 antagonist, raise fascinating questions. Furthermore, although not directly interacting with G proteins, NTS3 may modulate some of the G protein-dependent responses associated with NTS1 [46]. Moreover, NTS3 mRNA was detected in CHO cells [21].…”

Section: Introductionmentioning

confidence: 96%

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Interactions between neurotensin receptors and G proteins

Pélaprat

2006

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Abstract:Three neurotensin (NT) receptors have been cloned to date, two of which, NTS1 and NTS2, belonging 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 exerts agonist or antagonist activities depending on the considered NTS2-mediated pathway. 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Interactions between neurotensin receptors and G proteins

Pélaprat

2006

Peptides

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“…2d). Similarly, pretreatment of C57BL/6 mice with SR 48692 (2.5mg/kg, ip), a selective nonpeptide NTR1 antagonist that acts peripherally and centrally when administered either ip or by gavage 15 , decreased intestinal FA absorption following olive oil gavage (Fig. 2e).…”

mentioning

confidence: 86%

“…4c, d) that express NTR1 and 3 [similar to human intestinal cells (FHs 74 Int) and mouse intestinal mucosa (Extended Data Fig. 4e–g), and siRNA knockdown of either NTR1 or NTR3, which have been demonstrated to heterodimerize on the cell surface and to broaden the response range for NT signaling 15 , reduced NT-mediated FA absorption (Extended Data Fig. 4h, i).…”

mentioning

confidence: 98%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

219

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…Cette association fonctionnelle de la sortiline avec un autre récepteur membranaire n'est pas la première décrite. En effet, la sortiline forme également un complexe avec le récepteur 1 de la NT (NTR1, un récepteur à sept domaines transmembranaires) dans les cellules d'adénocarcinome de côlon humain HT29 [7]. Dans ce cas, la sortiline module l'intensité du signal induit par la NT puisque l'interaction sortiline-NTR1 diminue l'activité de la voie de signalisation intrinsèque du NTR1, activité qui fait intervenir les MAP kinases et la phospholipase C. D'autre part, dans les cellules microgliales humaines qui expriment la sortiline, la NT est capable d'activer la migration cellulaire par un mécanisme qui emprunte la voie de la protéine-kinase B (PI3-kinase) [8].…”

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