Role of vesicle-associated membrane protein 2 in exocytosis of glucagon-like peptide-1 from the murine intestinal L cell

Li, Samantha K; Zhu, Dan; Gaisano, Herbert Y.; Brubaker, Patricia L.

doi:10.1007/s00125-013-3143-2

Cited by 28 publications

(27 citation statements)

References 47 publications

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“…Although the precise mechanisms linking MEK/ERK activation to GLP-1 secretion requires further investigation, previous studies have demonstrated essential roles for rho guanosine 59-triphosphatase, cell division cycle 42, p21-activated kinase-1, and remodeling of the cortical F-actin cytoskeleton in this pathway (46). In line with this, actin-interacting SNARE (SNAP [Soluble NSF Attachment Protein] Receptor) proteins are also expressed in L-cells and are required for the exocytosis of GLP-1 (47,48). Further molecular analyses of intestinal L-cell signaling and exocytosis will be required to elucidate the exact pathways underlying the priming of GLP-1 secretory responses.…”

Section: Discussionmentioning

confidence: 83%

Ghrelin Is a Novel Regulator of GLP-1 Secretion

et al. 2014

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is a gastrointestinal L-cell hormone that enhances glucose-stimulated insulin secretion. Hence, strategies that prevent GLP-1 degradation or activate the GLP-1 receptor are used to treat patients with type 2 diabetes. GLP-1 secretion occurs after a meal and is partly regulated by other circulating hormones. Ghrelin is a stomach-derived hormone that plays a key role in wholebody energy metabolism. Because ghrelin levels peak immediately before mealtimes, we hypothesized that ghrelin plays a role in priming the intestinal L-cell for nutrient-induced GLP-1 release. The intraperitoneal injection of ghrelin into mice 15 min before the administration of oral glucose enhanced glucose-stimulated GLP-1 release and improved glucose tolerance, whereas the ghrelin receptor antagonist D-Lys GHRP-6 reduced plasma levels of GLP-1 and insulin and diminished oral glucose tolerance. The ghrelin-mediated improvement in glucose tolerance was lost in mice coinjected with a GLP-1 receptor antagonist as well as in Glp1r 2/2 mice lacking the GLP-1 receptor. The impaired oral glucose tolerance in diet-induced obese mice was also improved by ghrelin preadministration. Importantly, ghrelin directly stimulated GLP-1 release from L-cell lines (murine GLUTag, human NCI-H716) through an extracellular signal-related kinase 1/2-dependent pathway. These studies demonstrate a novel role for ghrelin in enhancing the GLP-1 secretory response to ingested nutrients.GLP-1 is a gastrointestinal hormone secreted from the enteroendocrine L-cell in response to nutrient ingestion. Once released into the circulation, GLP-1 elicits a potentiation of glucose-stimulated insulin secretion from the b-cells within the pancreatic islets, known as the incretin effect (1,2). The actions of incretin hormones, including GLP-1 as well as glucose-dependent insulinotropic peptide (GIP), on insulin secretion result in improved glucose clearance, and as such, incretin-based approaches are an important therapeutic tool in the treatment of patients with type 2 diabetes mellitus (T2DM). Current incretin therapies include long-acting GLP-1 receptor (GLP-1R) agonists and also inhibitors of incretin hormone degradation; however, GLP-1 secretagogues represent a potential third approach to enhancing incretin action in T2DM (1-3). GLP-1 secretion is regulated by a combination of nutrient-, neural-, and hormonal-activated pathways. Although nutrients have been shown to directly enhance GLP-1 release from the intestinal L-cell (4,5), the enteric and parasympathetic nervous systems (6,7) and other endocrine hormones are likely more critical mediators of the very rapid effect of meal ingestion on circulating levels of GLP-1. Several examples of the hormonal regulation of GLP-1 have been demonstrated. GIP enhances GLP-1 secretion from the rodent L-cell in vivo (7) and in vitro (8,9), whereas cholecystokinin appears to be more important in humans (10). The satiety factor, leptin, also stimulates GLP-1 release by rodent and human L-cells (11), as does the metabolic hormone, insulin (12). ...

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Section: Discussionmentioning

confidence: 83%

Ghrelin Is a Novel Regulator of GLP-1 Secretion

et al. 2014

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“…The exocytosis machinery is also similar, with both PC12 and ␣TC1-6 cells expressing the SNARE proteins syntaxin-1a, VAMP2, SNAP25 (34,48), and the SNARE-associated proteins Munc13-1 and Munc18-1 (49, 50), whereas AP-1 and AP-3 are expressed by PC12 and mouse ␣ cells (51). More recently, it has been shown that the GLUTag L cell model also expresses SNAP25, VAMP-1, -2 and -3, syntaxin-1a, and Munc18-1 (52). The literature therefore strongly supports the use of the PC12 cell line as a model for the sorting of proglucagon to the regulated secretory pathway in ␣ and L cells.…”

Section: Rationale For Using Pc12 Cells As a Model Of Hormonementioning

confidence: 99%

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Guizzetti¹,

McGirr

Dhanvantari

2014

Journal of Biological Chemistry

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Background:The constituent peptides of proglucagon contain ␣-helices that may target proglucagon to secretory granules. Results: Sorting of proglucagon processing intermediates is context-dependent, despite containing two sorted domains of glucagon and glucagon-like peptide 1. Conclusion: Proglucagon sorting is directed by two dipolar ␣-helices within glucagon and GLP-1. Significance: Hormone domains, rather than disordered prodomains, encode proglucagon sorting signals.

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“…Studies have confirmed the significant role of VAMP2 in exocytosis in non-neuron tissues, including surfactant secretion in the lungs 60 , glucagon-like peptide-1 exocytosis in murine intestinal L cells 25 , and zymogen granule secretion in pancreatic acini 61 . We speculated that suppression of SjVAMP2 might inhibit the normal cargo trafficking outside or inside the worm tegument, thus increasing the number of sensory organelles on the tegument to compensate the deficiency, and the subsequent malformation of over-sized sensory organelles with vacuolation, degeneration of the underlying syncytium.…”

Section: Discussionmentioning

confidence: 85%

“…VAMP2 (v-SNARE) has been extensively studied in neurons and confirmed to play a critical role in the fast exocytosis of neurotransmitter 21–23 . In non-neuronal tissues, VAMP2 is involved in the regulation of exocytosis including insulin secretion in pancreatic β-cells 24 , fusion of lytic granules in cytotoxic T-lymphocytes 25 , insulin-dependent translocation of GLUT4-containing vesicles in adipocytes 26, 27 and muscle regeneration in quiescent satellite cells 28, 29 .…”

Section: Introductionmentioning

confidence: 99%

Suppression of VAMP2 Alters Morphology of the Tegument and Affects Glucose uptake, Development and Reproduction of Schistosoma japonicum

Han

Jia

Hong

et al. 2017

Sci Rep

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Schistosomiasis caused by schsitosomes is a serious global public health concern. The tegument that surrounds the worm is critical to the schistosomes survival. The tegument apical membrane undergoes a continuous process of rupture and repair owing to membranous vacuoles fusing with the plasma membrane. Vesicle-associated membrane protein 2 (VAMP2), a member of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNAREs) is required for membrane fusion. Here, we used RNA interference (RNAi) to knock down the expression of VAMP2 of Schistosoma japonicum (SjVAMP2), and both real-time PCR and western blot analysis confirmed the suppression of this molecule, as well as the suppression of the transcript levels of schistosome glucose transporters (SGTP1 and SGTP4), and insulin receptors (SjIR1 and SjIR2). SjVAMP2-suppressed worms exhibited a lower viability, and phenotypic alterations were also observed in the tegument. Moreover, the glucose consumption of SjVAMP2-suppressed worms decreased significantly in 4 and 6 days, respectively, as well as a significant reduction in egg production. We also observed a significant reduction in worm burden and hepatic eggs burden in two independent RNAi experiment in vivo, and minor pathological changes in mice treated with SjVAMP2 specific small interfering (si)RNA. These findings reveal that SjVAMP2 may play important roles in the maintenance of tegument, glucose uptake, worm development and egg production in schistosomes.Schistosomiasis is a tropical parasitic disease that infects approximately 200 million people, and approximately 700 million people are at risk in 74 countries; it is caused by blood-dwelling fluke worms of the genus Schistosoma. Schistosomes have a complex life cycle that involves snails as intermediate hosts, and mammals (including humans) as definitive hosts 1, 2 . After cercariae penetrate the skin, they transform into young worms known as schistosomula, move into the bloodstream, and mature. After sexual maturation, adult schistosomes mate and lay eggs, and the eggs are primarily responsible for the pathological damage and disease transmission 3, 4 . Paired male and female schistosomes reside in the mesenteric veins of mammalian hosts and can survive for decades surrounded by the components of the immune system. Therefore, these organisms must have sophisticated mechanisms to evade host immune effectors and use host nutrients for metabolic processes and growth 5 .The entire worm is surrounded by a continuous cytoplasmic membrane, or syncytium, known as the tegument which is the direct interface between the parasite and its host 6 . The tegument is believed to be pivotal in evading hostile immune responses via antigenic mimicry 7,8 , proteolytic degradation of "attacking" host proteins 9 , rigid biophysical membrane properties 10 and a rapid tegumental membrane turnover 11,12 . Besides, the tegument is an important site of nutrient uptake from the host, such as glucose 13,14 , amino acids and cholesterol 15,16 , and also an ideal target sit...

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Role of vesicle-associated membrane protein 2 in exocytosis of glucagon-like peptide-1 from the murine intestinal L cell

Cited by 28 publications

References 47 publications

Ghrelin Is a Novel Regulator of GLP-1 Secretion

Ghrelin Is a Novel Regulator of GLP-1 Secretion

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Suppression of VAMP2 Alters Morphology of the Tegument and Affects Glucose uptake, Development and Reproduction of Schistosoma japonicum

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