Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway

Shi, Xuemei; Li, Xiaojie; Wang, Yi; Zhang, Keying; Zhou, Fuguo; Chan, Lawrence; Li, Defa; Guan, Xiaofei

doi:10.1152/ajpendo.00620.2010

Cited by 19 publications

(23 citation statements)

References 31 publications

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“…The identity of the majority of the cells that expressed VIP after responding to the GLP-2 stimulus as neurons is clear; this was confirmed using antibodies for the pan-neuronal markers HuC/D and ␤-tubulin at each step of the effects of GLP-2 on differentiation (9, 11). Similar demonstrations of GLP-2 activation and regulation of neuronal phenotype have been shown in vivo in the ENS and in cultures of embryonic hippocampal neurons (31,33). However, a similar GLP-2-linked Akt-activated pathway was demonstrated in cultured astrocytes from the CNS (37,38).…”

Section: Discussionsupporting

confidence: 72%

“…Cells were isolated from rat colon or mouse ileum; protocols were approved by the University of Calgary Animal Care Committee, following the Canadian Council on Animal Care guidelines. Using previously described methods, primary cultures of submucosal neurons were prepared (5,16,31). In brief, animals (rats and mice aged 2-3 mo) were anesthetized using halothane by inhalation (Halocarbon Products, River Edge, NJ) and then exsanguinated.…”

Section: Methodsmentioning

confidence: 99%

“…G protein-coupled receptor systems may act via variety of intracellular signaling pathways; previous studies used stable cell culture systems transfected with the receptor and suggested a GLP-2-coupled activation of adenylate cyclase (27,35,43). However, recent reports using cells that naturally express the receptor suggest that phosphatidylinositol 3-kinase-␥ (PI3K␥) and subsequent Akt phosphorylation are the intracellular pathways activated by 31). GLP-2 has also been reported to induce effects in the ErbB and neuregulin pathways, which also commonly regulate differentiation in neurons (8,39,41).…”

mentioning

confidence: 99%

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Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

Heuvel¹,

Wallace²,

Sharkey

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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de Heuvel E, Wallace L, Sharkey KA, Sigalet DL. Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-␥ signaling. Am J Physiol Endocrinol Metab 303: E994 -E1005, 2012. First published August 14, 2012; doi:10.1152/ajpendo.00291.2012.-Glucagon-like peptide 2 (GLP-2) is an enteroendocrine hormone trophic for intestinal mucosa; it has been shown to increase enteric neuronal expression of vasoactive intestinal polypeptide (VIP) in vivo. We hypothesized that GLP-2 would regulate VIP expression in enteric neurons via a phosphatidylinositol-3 kinase-␥ (PI3K␥) pathway. The mechanism of action of GLP-2 was investigated using primary cultures derived from the submucosal plexus (SMP) of the rat and mouse colon. GLP-2 (10 Ϫ8 M) stimulation for 24 h increased the proportion of enteric neurons expressing VIP (GLP-2: 40 Ϯ 6% vs. control: 22 Ϯ 5%). GLP-2 receptor expression was identified by immunohistochemistry on neurons (HuC/Dϩ) and glial cells (GFAPϩ) but not on smooth muscle or fibroblasts in culture. Over 1-4 h, GLP-2 stimulation of SMP increased phosphorylated Akt/Akt ratios 6.1-fold, phosphorylated ERK/ERK 2.5-fold, and p70S6K 2.2-fold but did not affect intracellular cAMP. PI3K␥ gene deletion or pharmacological blockade of PI3K␥, mammalian target of rapamycin (mTOR), and MEK/ ERK pathways blocked the increase in VIP expression by GLP-2. GLP-2 increased the expression of growth factors and their receptors in SMP cells in culture [IGF-1r (3.2-fold increase), EGFr (5-fold), and ErbB-2-4r (6-to 7-fold)] and ligands [IGF-I (1.5-fold), amphiregulin (2.5-fold), epiregulin (3.2-fold), EGF (7.5-fold), heparin-bound EGF (2.0-fold), ␤-cellulin (50-fold increase), and neuregulins 2-4 (300-fold increase) (by qRT-PCR)]. We conclude that GLP-2 acts on enteric neurons and glial cells in culture via a PI3K␥/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, and expression of receptors and ligands for the IGF-I and ErbB pathways.differentiation; extracellular signal-regulated kinase; ErbB; epidermal growth factor receptor; insulin-like growth factor I; neuregulin THE ENTERIC NERVOUS SYSTEM (ENS) is an important regulator of intestinal function and is understood primarily in terms of the control and integration of gastrointestinal motility, blood flow, and secretion (10,11,20). The role of the ENS in regulating other aspects of intestinal function, such as nutrient absorption and response to inflammation and injury, is becoming increasingly appreciated (18,23,32). The ENS is able to alter neuronal morphology, function, and the pattern of neurotransmitter expression in response to inflammation (17,33). Enteric neurons also undergo changes in neurochemical phenotype in pathophysiological states such as inflammation (22,29). The mechanisms that may regulate the phenotype and pattern of transmitter expression in the ENS in vivo are not well understood (5). In recent work, we have shown that glucagon-like peptide 2 (GLP-2), known as a trophic ...

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Section: Discussionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

Heuvel¹,

Wallace²,

Sharkey

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Here, we aimed at evaluating the potential benefit of GLP-2 on In non-ischemic models of different tissues, GLP-2 effects were mediated by the activation of the prosurvival kinases ERK1/2 [1] or by PI3K/Akt-mTOR signalling pathway [39]. Several studies have demonstrated that activation of G protein-coupled receptors may lead also to PI3K/Akt activation and cardioprotective effects [8,31].…”

Section: Discussionmentioning

confidence: 99%

Postconditioning with glucagon like peptide-2 reduces ischemia/reperfusion injury in isolated rat hearts: role of survival kinases and mitochondrial KATP channels

et al. 2012

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“…However, GLP-2R has the ability to couple to different G protein subunits and to activate multiple signalling pathways [18]. Studies using cells that naturally express the receptor suggest that phosphatidylinositol 3-kinase-γ[PI3Kγ] and subsequent Akt phosphorylation are the intracellular pathways activated by GLP-2 [19,20]. The enteric nervous system seems to be a key component in the GLP-2 action, and this was initially evident for one of the GLP-2's main activities, namely its ability to enhance intestinal epithelial growth.…”

Section: Introductionmentioning

confidence: 99%

GLP-2: What do we know? What are we going to discover?

Baldassano¹,

Amato²

2014

Regulatory Peptides

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The gastrointestinal tract The enteric nervous system Glucagon-like peptide 2 [GLP-2] is a 33-amino acid peptide released from the mucosal enteroendocrine L-cells of the intestine. The actions of GLP-2 are transduced by the GLP-2 receptor , which is localized in the neurons of the enteric nervous system but not in the intestinal epithelium, indicating an indirect mechanism of action. GLP-2 is well known for its trophic role within the intestine and interest in GLP-2 is now reviving based on the approval of the GLP-2R agonist for treatment of short bowel syndrome [SBS]. Recently it also seems to be involved in glucose homeostasis. The aim of this review is to outline the importance of neuroendocrine peptides, specifically of GLP-2 in the enteric modulation of the gastrointestinal function and to focus on new works in order to present an innovative picture of GLP-2.

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Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway

Abstract: X. Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway.

Cited by 19 publications

References 31 publications

Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling

Postconditioning with glucagon like peptide-2 reduces ischemia/reperfusion injury in isolated rat hearts: role of survival kinases and mitochondrial KATP channels

GLP-2: What do we know? What are we going to discover?

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