Glucagon GPCR Family Subtypes and Products

What Are Glucagon Receptors?

Glucagon receptors are a family of G protein-coupled receptors (GPCRs) comprised of six receptor subtypes: glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), gastric inhibitory polypeptide (GIP), growth hormone-releasing hormone (GHRH), and secretin receptors. Glucagon receptors play a major role in the regulation of blood glucose, insulin release, appetite regulation, and other various CNS effects. Glucagon receptor mutations in humans is associated with type II diabetes, hypoglycemia, and islet cell tumors. There are therapeutic applications for glucose receptors in treating diabetes.

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Glucagon Receptor Information

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GHRH

GIP

GLP-1

GLP-2

Glucagon

Secretin

Growth hormone-releasing hormone (GHRH), acting through the GHRH receptor GHRHR, plays a pivotal role in the regulation of GH synthesis and secretion in the pituitary. The isolated cDNA of the GHRHR predicted a 423-amino acid protein that has 7 putative transmembrane domains, characteristic of G protein- coupled receptors. It is a member of the secretin family of G protein-coupled receptors and has 47%, 42%, 35%, and 28% identity with receptors for vasoactive intestinal peptide, secretin, calcitonin and parathyroid hormone, respectively.

GIP (gastric inhibitory polypeptide) is released from the gastrointestinal tract, stimulates insulin secretion from pancreatic beta-cells, and plays a crucial role in the regulation of insulin secretion. Its receptor GIPR is expressed in the pancreas, stomach, small intestine, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelial cells, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several regions in the CNS. GIPR may have therapeutic potential in the treatment of type 2 diabetes and obesity.

Glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor for the endogenous insulinotropic peptide glucagon-like peptide-1 (GLP-1). GLP1R is expressed in pancreatic cells and the nervous system, and mediate the effects of GLP-1 in regulating glucose homeostasis through multiple mechanisms including direct actions on the endocrine pancreas and indirect activation of central nervous system controlling gastric emptying, satiety, and body weight. In the brain, receptor activation elicits neurotrophic actions through protection against metabolic and oxidative insults. GLP1R is also implicated in plasticity, memory, and learning. Thus, GLP1R is a potential therapeutic target for both cognitive-enhancing and neuroprotective agents and in the treatment of stroke and Parkinsonism.

Glucagon-like peptide 2 receptor belongs to the glucagon-secretin receptor superfamily of GPCRs. The human GLP-2 receptor gene is localized on chromosome 17p13.3. The GLP-2 receptor exhibits ~50% amino acid identity with GLP-1 receptor. GLP-2 receptor binds to Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive hormone and activates adenylate cyclase pathway and to a lesser extent activates MAP kinases. GLP-2 receptors are found in the central nervous system and gastrointestinal tract, with the highest expression levels in jejunum. The principal role of GLP-2 receptors appears to be the maintenance of the growth, nutrient absorption, cell proliferation, apoptosis, mucosal blood flow and suppressing gastric motility and secretion. The regenerative and cytoprotective properties of GLP-2 contribute to its therapeutic potential for the treatment of patients with intestinal disease. Recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is important. A detailed delineation of the signaling pathways activated by gut peptide GPCRs, as exemplified by GLP-1and GLP-2, may provide new therapeutic targets for the treatment of human disorders such as diabetes and intestinal disease, respectively.

The human glucagon receptor GCGR mediates the action of the pancreatic peptide hormone glucagon. Glucagon regulates blood glucose via control of hepatic glycogenolysis and gluconeogenesis and via regulation of insulin release from the β cell. Type 2 diabetes is characterized by inappropriate regulation of hepatic glucose production, which is due to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and anti-glucagon antibodies have demonstrated the potential of glucagon receptor antagonism as a treatment for type 2 diabetes. Glucagon also elicits various effects in extrahepatic tissues, including adipose tissue, kidney, heart, pancreatic β cells, gastrointestinal tract, thyroid and central nervous system.

Human secretin receptor (gene name SCTR) is a G-protein-coupled receptor, a member of the class B GPCR subfamily. Secretin receptor binds to peptide secretin and the pituitary adenylate cyclase activating peptide. It was the first receptor that was cloned in the class B family of GPCRs. Secretin receptor is also regulated by peptide hormones from the glucagon hormone family. The receptor activates two distinct intracellular signaling pathways, i.e. the adenyl cyclase and the phosphatidyl-inositol calcium pathways. Northern blot analysis has shown that the secretin receptor is expressed in pancreas, kidney, small intestine, lung, liver, and in trace levels in the brain, heart and ovary. Secretin-receptor mRNA is abundant in all gastrinomas, enriched in one specific variant. Knockout of secretin receptor was shown to reduce large cholangiocyte hyperplasia. Studies have also demonstrated the potential use of secretin as a therapy for ductopenic liver diseases.

Glucagon Cell Lines

Receptor Family	Receptor	Species	Parental	Stable Cell Lines	Division-Arrested Cells	Membranes
Glucagon	GHRH	human	HEK293T	C1291	DC1291	MC1291
	GIP	human	HEK293T	C1290	DC1290	MC1290
	GIP	human	HEK293T β-Arrestin2	CA1290	DCA1290	MCA1290
	GIP	human	HEK293T β-Arrestin2	CA1290BA1	DCA1290BA1	MCA1290BA1
	GIP	mouse	HEK293T	Cm1290	DCm1290	MCm1290
	GIP	rat	HEK293T	Cr1290	DCr1290	MCr1290
	GIP	dog	HEK293T	Cd1290	DCd1290	MCd1290
	GIP	dog	HEK293T	Cd1290a	DCd1290a	MCd1290a
	GIP	rabbit	HEK293T	Cb1290	DCb1290	MCb1290
	GIP	rhesus monkey	HEK293T	Cpr1290	DCpr1290	MCpr1290
	GIP	rhesus monkey	HEK293T	Cpr1290a	DCpr1290a	MCpr1290a
	GIP	ferret	HEK293T	Cf1290	DCf1290	MCf1290
	GIP	ferret	HEK293T	Cf1290a	DCf1290a	MCf1290a
	GLP-1	human	HEK293T	C1267	DC1267	MC1267
	GLP-1	human	CHO-K1	C1267-1	DC1267-1	MC1267-1
	GLP-1	human	CHO-K1	C1267-1a	DC1267-1a	MC1267-1a
	GLP-1	human	CHO-K1 β-Arrestin2	CA1267-1	DCA1267-1	MCA1267-1
	GLP-1	human	HEK293T β-Arrestin2	CA1267BA2	DCA1267BA2	MCA1267BA2
	GLP-1	cynomolgus monkey	CHO-K1	Cpc1267-1	DCpc1267-1	MCpc1267-1
	GLP-1	cynomolgus monkey	CHO-K1	Cpc1267-1a	DCpc1267-1a	MCpc1267-1a
	GLP-1	rat	CHO-K1	Cr1267-1	DCr1267-1	MCr1267-1
	GLP-1	dog	CHO-K1	Cd1267-1	DCd1267-1	MCd1267-1
	GLP-1	mouse	CHO-K1	Cm1267-1	DCm1267-1	MCm1267-1
	GLP-1	mouse	CHO-K1	Cm1267-1a	DCm1267-1a	MCm1267-1a
	GLP-2	human	HEK293T	C1268	DC1268	MC1268
	GLP-2	rat	HEK293T	Cr1268	DCr1268	MCr1268
	Glucagon	human	HEK293T	C1266	DC1266	MC1266
	Glucagon	human	HEK293T	C1266A	DC1266A	MC1266A
	Glucagon	human	CHO-K1	C1266-1	DC1266-1	MC1266-1
	Glucagon	human	CHO-K1	C1266-1a	DC1266-1a	MC1266-1a
	Glucagon	human	CHO-K1 β-Arrestin2	CA1266-1	DCA1266-1	MCA1266-1
	Glucagon	cynomolgus monkey	CHO-K1	Cpc1266-1	DCpc1266-1	MCpc1266-1
	Glucagon	cynomolgus monkey	CHO-K1	Cpc1266-1a	DCpc1266-1a	MCpc1266-1a
	Glucagon	cynomolgus monkey	HEK293T	Cpc1266	DCpc1266	MCpc1266
	Glucagon	cynomolgus monkey	HEK293T	Cpc1266a	DCpc1266a	MCpc1266a
	Secretin	human	CHO-K1	C1228-1	DC1228-1	MC1228-1