Glucagon Receptor

A glucagon receptor is a G protein-coupled receptor found mainly in the liver. These receptors bind to the hormone glucagon made by the pancreas, and they cause the break down of glycogen, a storage form of sugar.

110084-95-2
LGD-6972
1207989-09-0
Exendin 9-39
133514-43-9
1393124-08-7
1393124-08-7
1488363-78-5
Adomeglivant
1488363-78-5
CP 316819
186392-43-8
186392-65-4
Ingliforib
186392-65-4
186430-23-9
CP-320626
186430-23-9
L-168,049
191034-25-0
202855-56-9
BAY-27-9955
202855-56-9
202917-17-7
202917-17-7
202917-18-8
202917-18-8
B0084-474685
Liraglutide
204656-20-2
Taspoglutide
275371-94-3
GRA Ex-25
307983-31-9

Background


The glucagon receptor (GR) is a cell surface G protein-coupled receptor (GPCR) that is responsive to glucagon. As a primary regulator of glucose metabolism, GR stimulation activates adenylyl cyclase, which in turn increases cAMP levels, leading to the activation of PKA. Like many other GPCRs, the GR may be capable of intrinsic activity and basal activation mediated by nucleoside-diphosphate kinase or adenylyl cyclases. The downstream effectors activated by the GR encompass a broad signaling and transcriptional network that includes cAMP, cAMP response element-binding protein (CREB), hepatic nuclear factors (HNF), the glucocorticoid receptor, and MAPKs. Besides the regulation of lipid metabolism, glucagon signaling through the GR stabilizes plasma cholesterol levels, carbohydrate metabolism, and triglyceride production.

The GR is highly conserved in primary and secondary structure. Protein alignment (utilizing the ExPASy Proteomics Server) of the human GR, which is 477 amino acid residues, and the mouse/rat GR, which are each 485 amino acid residues, indicate approximately 80% homology between GR sequences for the human GR versus mouse/rat GRs. This alignment result is consistent with previous reports of primary structure similarity between the human and rat GRs. In comparison, there is 94% homology between the mouse and rat GR..

GR is expressed mainly in the liver and kidney, and at much lower levels in the intestinal tract, heart, adipose tissue, spleen, thymus, adrenals, β cells of the pancreatic islets, and some areas of the brain. In the liver, GR mRNA is found predominantly in the periportal, more highly aerobic area of the liver, which is the region where the glucagonstimulated processes of glycogenolysis and gluconeogenesis predominantly occur. GR has been found to be expressed in different cell types of the liver, including parenchymal cells (hepatocytes) and in some non-parenchymal cells.

Diabetes

The role of glucagon/GR signaling in diabetes is one of the many areas of glucagon research that remains to be fully elucidated. Diabetic conditions are associated with hyperglycemia and current knowledge suggests that glucagon may be a key component that contributes to the elevated blood glucose condition seen in patients with type 2 diabetes. Additionally, several papers have also reported that hyperglycemia can lead to cholestasis, which eventually can lead to liver cancer. As increased glucagon levels contribute to the pathophysiology of hyperglycemia in type 2 diabetes patients, blocking GR activity is a possible therapeutic target for type 2 diabetes. One area of research is in the development of antagonists of GR that can be used to inhibit glucagon-mediated biological effects.

Liver Disease

Changes in GR levels have been reported for certain conditions, including steatosis of the liver. In these studies, high fat, diet-induced hepatic steatosis in rat hepatocytes led to increases in endosomal and lysosomal GR content, and a reduction of GR in the plasma membrane, suggesting that desensitization and downregulation of the receptor may occur in some liver diseases. These effects were correlated with an increase in PKC-α, suggesting a role for PKC-α in desensitization and downregulation of GR, and reduction in total and membrane protein levels of GR. As noted above, hyperglycemia is associated with the development of cholestasis, thus, the hyperglycemic effects of glucagon due to higher levels of glucagon in diabetics could contribute to the onset of liver disease. Increased plasma glucagon levels have been reported for patients with cirrhosis of the liver and have been attributed to abnormal degradation of glucagon in the liver due to the diseased condition of the liver or hypersecretion of glucagon occurring for unknown reasons. Therefore, the increases in glucagon seen with liver cirrhosis can further exacerbate other conditions, such as hyperglycemia that is often seen with type 2 diabetes (discussed above).

Reference:

Nguyen, Amy C. Analysis of the Role of Glucagon in Hepatocellular Carcinoma Cell Growth, Invasion, and Migration and the Regulation of Glucagon Receptor Signaling. Diss. THE GEORGE WASHINGTON UNIVERSITY, 2011.

Ceniccola, Kristin E. The Glucagon Receptor Functions as a Tumor Suppressor in Hepatocellular Carcinoma. Diss. THE GEORGE WASHINGTON UNIVERSITY, 2014.