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Phospholipase C-ε links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans.
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Who cites it
40 citing papers in PubMed, 77 citations in OpenAlex.
- Altered GScience advances · 2026Article
- GLP-1 Receptor Agonists in Chronic Inflammatory Skin Diseases: Immunometabolic Mechanisms and Translational Perspectives.Pharmaceutics · 2026Review
- Structural insights into Phospholipase Cε activity and regulation.The Journal of biological chemistry · 2026Review
- Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene.Nature communications · 2025Article
- Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes.Comprehensive Physiology · 2023Article
- PACAP and acetylcholine cause distinct Ca2+ signals and secretory responses in chromaffin cells.The Journal of general physiology · 2023Article
- The effect of forskolin and the role of Epac2A during activation, activity, and deactivation of beta cell networks.Frontiers in endocrinology · 2023Article
- Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon.The Journal of biological chemistry · 2022Article
- Review
- Review
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- Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3',5'-adenosine monophosphate (Epac) in murine skeletal muscle.Scientific reports · 2019Article
- Reduced Expression ofFrontiers in endocrinology · 2019Article
- Regulation of cAMP accumulation and activity by distinct phosphodiesterase subtypes in INS-1 cells and human pancreatic β-cells.PloS one · 2019Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- PACAP signaling in stress: insights from the chromaffin cell.Pflugers Archiv : European journal of physiology · 2018Review
- Alpha TC1 and Beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts.Scientific reports · 2017Article
- Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.Bioorganic & medicinal chemistry letters · 2017Review
- Sucralose activates an ERK1/2-ribosomal protein S6 signaling axis.FEBS open bio · 2017Article
- Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.Pharmacological reviews · 2016Review
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is potentiated by cAMP-elevating agents, such as the incretin hormone glucagon-like peptide-1 (GLP-1), and cAMP exerts its insulin secretagogue action by activating both protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Although prior studies of mouse islets demonstrated that Epac2 acts via Rap1 GTPase to potentiate GSIS, it is not understood which downstream targets of Rap1 promote the exocytosis of insulin. Here, we measured insulin secretion stimulated by a cAMP analog that is a selective activator of Epac proteins in order to demonstrate that a Rap1-regulated phospholipase C-epsilon (PLC-ε) links Epac2 activation to the potentiation of GSIS. Our analysis demonstrates that the Epac activator 8-pCPT-2'-O-Me-cAMP-AM potentiates GSIS from the islets of wild-type (WT) mice, whereas it has a greatly reduced insulin secretagogue action in the islets of Epac2 (-/-) and PLC-ε (-/-) knockout (KO) mice. Importantly, the insulin secretagogue action of 8-pCPT-2'-O-Me-cAMP-AM in WT mouse islets cannot be explained by an unexpected action of this cAMP analog to activate PKA, as verified through the use of a FRET-based A-kinase activity reporter (AKAR3) that reports PKA activation. Since the KO of PLC-ε disrupts the ability of 8-pCPT-2'-O-Me-cAMP-AM to potentiate GSIS, while also disrupting its ability to stimulate an increase of β-cell [Ca2+]i, the available evidence indicates that it is a Rap1-regulated PLC-ε that links Epac2 activation to Ca2+-dependent exocytosis of insulin.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.