cAMP-dependent Protein Kinase and Ca2+Influx through L-type Voltage-gated Calcium Channels Mediate Raf-independent Activation of Extracellular Regulated Kinase in Response to Glucagon-like Peptide-1 in Pancreatic β-Cells

Gomez, Edith; Pritchard, Catrin; Herbert, Terence P.

doi:10.1074/jbc.m209165200

Cited by 144 publications

(131 citation statements)

References 43 publications

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“…Alternatively, calcium may act locally near the membrane and close to the mouth of the L-type voltage-dependent calcium channel. A model has been proposed in which calcium binds calmodulin tethered to the channel, causing it to associate with the IQ motif of the channel; this association then leads to the activation of the Ras-mitogen-activated extracellular signal-regulated kinase kinase-ERK1/2 MAPK signalling pathway and sustained CREB Ser119 phosphorylation [30,31]. In addition to these kinases, the calcium/ calmodulin-dependent protein phosphatase calcineurin is also required for CREB activation by membrane depolarisation [3,16,17].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

et al. 2005

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Aims/hypothesis: The activation of the transcription factor cyclic AMP response element binding protein (CREB) by protein kinase A is inhibited by the human orthologue of the mitogen-activated protein kinase, dualleucine-zipper-bearing kinase (DLK) in teratocarcinoma cells. However, pancreatic beta cells are electrically excitable and a major pathway regulating CREB in these cells is membrane depolarisation, leading to calcium influx and activation of the calcium/calmodulin-dependent protein phosphatase calcineurin. Therefore, the effect of DLK on CREB activity induced by membrane depolarisation was investigated in the beta cell line HIT. Materials and methods: Reporter gene assays and biochemical techniques were used. Results: RT-PCR, Western blot analysis and immunohistochemistry demonstrated the expression of DLK in HIT cells and primary mouse islets. In transient transfection experiments, DLK inhibited both GAL4-CREB activity induced by membrane depolarisation, and transcription directed by the CREB binding site, the cyclic AMP response element. Furthermore, DLK inhibited the transcriptional activity conferred by the CREB coactivator, CREB binding protein, both under basal conditions and after membrane depolarisation. DLK was also effective in response to glucose, the most potent physiological stimulus and known to cause membrane depolarisation of beta cells. Inhibition of calcineurin enhanced DLK activity, whereas overexpression of calcineurin reduced the inhibition by DLK of transcription directed by cyclic AMP response element after membrane depolarisation. Conclusions/interpretation: These results demonstrate a calcineurin-sensitive inhibition by DLK of CREB activity after membrane depolarisation in pancreatic islet beta cells. This inhibition may, at least partially, be mediated at the coactivator level. The results thus suggest that DLK plays a role in the regulation of beta cell function, including insulin gene transcription and beta cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

et al. 2005

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“…Activation of ERK1/2 occurs via phosphorylation and translocation to the nucleus and ERK1/2 already present in the nucleus is phosphorylated upon stimulation. Glucose stimulation has been demonstrated to activate both isomers of ERK in β cells Gomez et al, 2002;Khoo and Cobb, 1997). Phosphorylation of ERK1/2 in response to GLP-1 treatment has been demonstrated in several insulinoma cell lines Gomez et al, 2002) and more recently by GLP-1 (Trumper et al, 2005) and Ex-4 in human islets.…”

Section: Mapk and Pi3 Kinase Related Pathwaysmentioning

confidence: 99%

“…Glucose stimulation has been demonstrated to activate both isomers of ERK in β cells Gomez et al, 2002;Khoo and Cobb, 1997). Phosphorylation of ERK1/2 in response to GLP-1 treatment has been demonstrated in several insulinoma cell lines Gomez et al, 2002) and more recently by GLP-1 (Trumper et al, 2005) and Ex-4 in human islets. The earlier studies in the insulinoma cell lines reported conflicting data indicating either a Raf/Ras-independent mechanism or inconsistent Raf activation due most probably to the different cell types used in the experiments.…”

Section: Mapk and Pi3 Kinase Related Pathwaysmentioning

confidence: 99%

“…Recent studies have shown that activation of MAPK-related pathways can occur downstream of GLP-1R-induced cAMP activation. Specifically, the extracellular signal regulated kinases (ERK) 1 and 2 have been shown to be activated in a Ca 2+ Gomez et al, 2002) and cAMP dependent manner . ERK1 and ERK2 are the terminal enzymes in a three-kinase cascade, consisting of the Raf kinases that activate the MAP/ERK kinases, MEK1 and MEK2 that, in turn, activate ERK1/2.…”

Section: Mapk and Pi3 Kinase Related Pathwaysmentioning

confidence: 99%

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Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

583

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…Glucose and GLP-1 have been shown to activate ERK in numerous beta cell lines and in murine islets [3][4][5]. How-ever, the published results are inconsistent with respect to whether this activation is dependent on [3] or independent of [4,5] Ras and Raf kinases.…”

Section: Introductionmentioning

confidence: 99%

The Rap–B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells

et al. 2005

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Aims/hypothesis: Glucose and glucagon-like peptide-1 have been shown to activate extracellular signalregulated kinase (ERK) and phosphoinositide 3-kinase in beta cells. We examined the contributions of the small GTPases Rap and Ras and the serine-threonine kinases BRaf and Raf-1 to the activation of these kinases in human islet cells. Methods: The expression of Rap, Ras, B-Raf and Raf-1 in human islets was examined by immunohistochemistry and immunoblotting. Human islets were incubated in glucose at concentrations of 2.5 and 15 mmol/l and were stimulated with 10 nmol/l glucagon-like peptide-1. The activation of ERK and Raf kinases was examined by phosphorylation-specific antibodies and immuno-complexed kinase assays. The activation of Rap and Ras was determined by pull-down assays. Stimulation of phosphoinositide 3-kinase was detected by immuno-complexed lipid kinase assays. Results: Extracellular-regulated kinase and protein kinase B (a downstream target of phosphoinositide 3-kinase) were activated in islets stimulated with glucose and glucagon-like peptide-1. In these islets, the Rap-B-Raf signalling pathway was activated preferentially compared with Ras and Raf-1, and activated Rap and B-Raf mediated ERK stimulation in kinase assays in vitro. In addition, Rap rather than Ras mediated activation of phosphoinositide 3-kinase in islets stimulated with glucose and glucagon-like peptide-1. Conclusions/interpretation: In human islet cells, glucose and glucagon-like peptide-1 activate the Rap and BRaf signalling module, which mediates ERK activation in assays in vitro. Rap also activates phosphoinositide 3-kinase, delineating central roles for Rap and B-Raf as therapeutic targets for beta cell growth in diabetes mellitus.

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cAMP-dependent Protein Kinase and Ca2+Influx through L-type Voltage-gated Calcium Channels Mediate Raf-independent Activation of Extracellular Regulated Kinase in Response to Glucagon-like Peptide-1 in Pancreatic β-Cells

Cited by 144 publications

References 43 publications

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line

Mechanisms of action of glucagon-like peptide 1 in the pancreas

The Rap–B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells

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