Target Background

The glucagon receptor (GCGR) is a class B G-protein-coupled receptor (GPCR) that mediates the actions of the peptide hormone glucagon. GCGR is primarily expressed in the liver, with additional expression in kidney, adipose tissue, heart, and certain regions of the central nervous system. Its tissue distribution reflects its central role in glucose and lipid homeostasis, as well as broader metabolic regulation.

Upon binding to glucagon, GCGR couples predominantly to Gs proteins, stimulating adenylate cyclase and elevating intracellular cAMP levels. This leads to activation of downstream effectors such as protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factors (Epac). In hepatocytes, GCGR signaling promotes glycogenolysis and gluconeogenesis, thereby increasing blood glucose levels during fasting. Beyond the liver, GCGR activity influences lipolysis in adipose tissue, modulates cardiovascular function, and contributes to energy expenditure through thermogenic pathways.

Pharmacologically, GCGR has been a long-standing target for metabolic disorders. Antagonists of GCGR have been investigated for type 2 diabetes due to their ability to reduce hepatic glucose output and improve glycemic control. More recently, GCGR agonism has gained attention in obesity research, particularly in the context of multi-receptor agonists that combine GLP-1R and GCGR activity to enhance weight loss and energy expenditure. This dual approach aims to balance the hyperglycemic effects of GCGR activation with the insulinotropic actions of GLP-1R, creating synergistic therapeutic outcomes. With its pivotal role in hepatic glucose metabolism and emerging significance in energy balance, GCGR remains a major focus of incretin- and glucagon-based drug discovery.