GCGR Specific Neutra™ Antibody Products

Glucagon Receptor (GCGR) is a crucial membrane protein comprised of 477 amino acids and categorized under the family B G protein-coupled receptors. The liver and kidney are where it is primarily expressed. GCGR binds with glucagon to regulate glucose homeostasis in vivo, making it an important target in type 2 diabetes (T2D). Research indicates that the peptide connecting the extracellular and transmembrane structural domains of GCGR plays a pivotal role in controlling receptor activation. Upon binding with the ligand, this peptide detaches from the receptor, prompting a conformational shift that activates the receptor and initiates signaling to regulate downstream effector activity.

Its Gene ID: 2642, UniProtKB ID: P47871, and OMIM ID: 138033.

Fig.1 Cryo-EM structure of the ligand-free GCGR.^{1, 3}

GCGR-Related Signaling Pathway

Activation of GCGR by glucagon triggers the upregulation of genes associated with gluconeogenesis, glycogenolysis, and fatty acid metabolism primarily through mediating the downstream cyclic-adenosine monophosphate (cAMP)-protein kinase A signaling pathway. Additionally, GCGR activation stimulates the phospholipase C-inositol triphosphate (PLC-IP3) pathway, further contributing to the expression of gluconeogenesis-related genes. In the pathogenesis of T2D, insufficient insulin secretion and insulin resistance in the early stages lead to a dysfunctional balance between insulin and glucagon. Dysregulated glucagon secretion triggers hyperglucagonemia, which further causes the liver to generate excess glucose.

Fig.2 Glucagon activates GCGR to mediate downstream signaling pathways.^{2, 3}

GCGR-Based Therapies for Diabetes

GCGR plays a crucial role in maintaining blood glucose homeostasis. Several emerging therapies based on GCGR are currently in preclinical and clinical development stages.

• GCGR Antagonists

Several GCGR antagonists have been developed to improve glucose control, insulin secretion, and glucose tolerance in animals, displaying significant efficacy in patients with T2D. Nevertheless, their clinical trials have faced challenges. These antagonists are hindered by adverse effects including increased LDL-c and ALT levels, restricting their application in clinical settings.

• GCGR Antisense Oligonucleotides (GR-ASO)

GR-ASO is a potent antagonist that targets GCGR, effectively inhibiting the action of glucagon by reducing the expression of GCGR mRNA. Promising results have been demonstrated in many projects, showcasing their ability to modulate glucagon-induced glucose production and hepatic fluctuations. This data underscores the potential of GR-ASO as a viable treatment option for individuals with T2D.

• GCGR Monoclonal Antibodies (mAbs)

Monoclonal antibodies (mAbs) offer a range of benefits including high specificity, effective targeting, and relatively easy to source, making them a key focus in drug development. Anti-GCGR mAbs have shown remarkable efficacy in treating diabetes, with studies demonstrating their ability to normalize blood glucose levels in both mice and patients with T1D. These mAbs also exhibit strong hypoglycemic effects in animal models of T2D. In addition, they have the potential to induce β cell regeneration by promoting the transdifferentiation of pancreatic cells. Overall, anti-GCGR mAbs show promise in improving glycemic control and present exciting opportunities for further research.

Creative Biolabs offers over 20 different anti-GCGR antibody products. These antibodies include recombinant antibodies and neutralizing antibodies, which can be used for 11 different applications. Custom services based on antibodies are also available to meet your specific needs.

REFERENCES

1. Cong, Zhaotong, et al. "Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins." Cell Discovery 10.1 (2024): 18.
2. Demir, Sevgican, et al. "Emerging targets in type 2 diabetes and diabetic complications." Advanced Science 8.18 (2021): 2100275.
3. Distributed under open access license CC BY 4.0, without modification.