Glucagon GPCR Assays
Background of Glucagon Receptors
Glucagon receptors are a family of G protein-coupled receptors, natural ligands of which are glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP), gastric inhibitory polypeptide (GIP), growth hormone-releasing hormone (GHRH), and secretin, respectively. Glucagon is a peptide hormone involved in suppressing insulin secretion, generated by islet A cells, brain, and the gastrointestinal tract. Similar to glucagon, GLP-1 and GLP are also peptide hormones that originated from a common prohormone precursor, proglucagon. GIP is a polypeptide generated and secreted from enteroendocrine K-cells in the duodenum and jejunum, playing a glucose-dependent inhibitory role. By binding to GIP, GIP receptors on islet β-cells coupling the G proteins enhance the glucose-dependent insulin secretion, which is crucial for maintaining the normal glucose level. Oversecreting of GHRH leads to pituitary somatotroph cell hyperplasia and inappropriate patterns of growth. Secretin is a compound secreted from the proximal intestinal mucosa. It plays a role in the activation of pancreatic fluid secretion.
Fig.1 Structure of the class B human glucagon G protein-coupled receptor. (Bataille, 2019)
Distribution and Function of Glucagon Receptors
Glucagon receptors are mainly distributed in the liver, fetal, pancreas, kidney, and lung, and throughout the gastrointestinal tract. They are involved in glycogenolysis, gluconeogenesis, and lipolysis. GLP-1 receptors are responsible for the stimulation of pancreatic insulin release, basal TSH release from thyrotropes and α-TSH cells, as well as stimulation of neurons of the hypothalamo-pituitary-adrenocortical axis, and oxytocinergic neurons of the hypothalamic-neurohypophysial tract primarily expressed in the pancreas, lung, brain, heart, kidney, and stomach. GLP-2 receptors are located throughout the gastrointestinal tract involved in cell proliferation, nutrient digestion, and absorption. GIP receptors are distributed in umbilical, aortic, and pulmonary artery endothelial cells. The absence of GIP receptors may cause diabetes. GHRH receptors are principally located in the pituitary and kidney stimulating pituitary somatotroph cell proliferation and growth hormone release. Secretin receptors are found in the gastrointestinal tract and lung activating GABA release.
Subtypes and Mechanisms of Glucagon Receptors
The family of glucagon receptors contains six subtypes of G protein-coupled receptors, including glucagon receptor, GLP-1 receptor, GLP-2 receptor, GIP receptor, GHRH receptor, and secretin receptor, all of which are mediated by Gs proteins for the signal transduction, stimulating adenylyl cyclase.
| Receptor | Gene | Mechanism | Agonists | Antagonists |
| Glucagon receptor | GCGR |
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| GLP-1 receptor | GLP1R |
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| GLP-2 receptor | GLP2R |
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| GIP receptor | GIPR |
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| GHRH receptor | GHRHR |
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| Secretin receptor | SCTR |
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Assay List of Glucagon Receptors
Creative Biolabs can provide a range of assays of glucagon receptors. You can choose the assay in the list or contact us for more information:
| Assay No. | Assay Name | Host Cell | Assay Type | Datasheet |
|---|---|---|---|---|
| Calcium Flux Assay | ||||
| S01YF-1122-KX503 | Magic™ Human SCTR In Vitro Calcium Flux Assay | CHO-K1 | Calcium Flux Assay | |
Published Data
| Paper Title | Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP |
| Journal | Journal of biological chemistry |
| Published | 2019 |
| Abstract | GPCRs for glucagon receptor and GLP-1R are normally considered to be highly selective for glucagon and GLP-1. In the volume-restricted microenvironment of the islets of Langerhans, glucagon secreted from pancreatic α-cells may accumulate at high concentrations to exert promiscuous effects at the β-cell GLP-1R. High doses of systemic administration of glucagon receptor or GLP-1R agonists and antagonists may lead to lead to off-target effects on other receptors. The study used molecular modeling to evaluate data derived from microplate high-throughput fluorescence resonance energy transfer (FRET) assays that detect cAMP as a read-out for glucagon receptor and GLP-1R activation. The study investigated the agonistic or antagonistic effects of glucagon, des-His1-[Glu9]glucagon, exendin(9–39) (Ex(9–39)), hybrid peptide GGP817, LY2409021, and MK 0893 on both GPCRs. |
| Result |
The results indicated that the glucagon was a nonconventional GLP-1R agonist, which was also inhibited by the GLP-1R orthostatic antagonist exendin(9–39) (Ex(9–39)). LY2409021 and MK 0893 were allosteric inhibitors of glucagon, which antagonized glucagon and GLP-1 action at the GLP-1R. However, des-His1-[Glu9]glucagon antagonized glucagon action at the glucagon receptor, while having only a few inhibitory actions at glucagon or GLP-1 at the GLP-1R. The study validated a dual agonist action of glucagon at the glucagon receptor and GLP-1R combining Ex(9–39) with des-His1-[Glu9]glucagon in INS-1 832/13 cells. Hybrid peptide GGP817 containing glucagon fused to a fragment of peptide YY (PYY) has been investigated to exert as a triagonist at the glucagon receptor, GLP-1R, and neuropeptide Y2 receptor (NPY2R). This study has provided a new way of thinking that the glucagon receptor and GLP-1R agonists and antagonists may exert promiscuous actions at other GPCRs.
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Fig.2 Glucagon and LY2409021 both target glucagon and GLP-1 receptors. (Chepurny, 2019)
References
- Bataille D.; et al. Glucagon receptor family (version 2019.3) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE. 2019, 2019(3).
- Chepurny, O. G.; et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP. Journal of Biological Chemistry. 2019, 294(10): 3514-3531.
