The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization

Lok, Si; Kuijper, Joseph L.; Jelinek, Laura; Kramer, Janet; Whitmore, Theodore E.; Sprecher, Cindy A.; Mathewes, Shannon; Grant, Francis James; Biggs, S; Rosenberg, Gary B.; Sheppard, Paul O.; O׳Hara, Patrick J.; Foster, Donald C.; Kindsvogel, Wayne

doi:10.1016/0378-1119(94)90545-2

Cited by 115 publications

(134 citation statements)

References 23 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…To assess the effect of Cpd 1 under these conditions, we first labeled endogenous glycogen with the aid of [2-13 C]pyruvate. Administration of [2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate (6.7 mmol/l) over the entire duration of experiment (ϳ150 min) resulted in a steady increase in the amount of glycogen, as indicated by changes in the levels of [ 13 C]glycogen in these livers (Fig. 4).…”

Section: Inhibition Of Glycogenolysis In Human Hepatocytesmentioning

confidence: 95%

“…Other closely related members of the family include the receptors for glucagonlike peptide 1 and glucose-dependent insulinotropic peptide (GIP). Glucagon signals by binding to the receptor, which leads to activation of adenylyl cyclase and an increase in intracellular cAMP levels (12). In addition, the GCGR also couples to an intracellular Ca 2ϩ -mediated pathway (13).…”

mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

et al. 2004

View full text Add to dashboard Cite

Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125 I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 ؎ 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a K DB of 81 ؎ 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagoninduced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo. Diabetes 53

show abstract

Section: Inhibition Of Glycogenolysis In Human Hepatocytesmentioning

confidence: 95%

mentioning

confidence: 99%

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

et al. 2004

View full text Add to dashboard Cite

show abstract

“…The PCR step was conducted on 5 ml of the prepared cDNA in 9 mmol/l TRIS HCl pH 8.3, 45 mmol/l KCl, 2 mmol/l MgCl 2 , 100 mmol/l dNTP, 20 pmoles of the 3'-and 5'-primers and 2.5 units of Taq polymerase (Perkin Elmer). Specific primers were designed to anneal with codons 199±206/422±429 for the published sequence of the human liver glucagon receptor [27], codons 203±209/424±431 for the human GLP-1R [25] and codons 195±202/377±384 for the human GIP-R [26], yielding products with expected length (689, 684 and 568 bp respectively). We used B-actin primers, designed to anneal with codons 249±255/388±244 of human b-actin (gene accession number NM001 101) as an internal control to evaluate RNA quality.…”

Section: Methodsmentioning

confidence: 99%

Glucagon receptors on human islet cells contribute to glucose competence of insulin release

et al. 2000

View full text Add to dashboard Cite

Previous studies on rat beta cells in vitro have suggested that insulin release is synergistically regulated by signalling molecules derived from glucose metabolism on the one hand and adenylate cyclase stimulation by glucagon or related peptides on the other [1±3]. In rodent beta cells, regulation of the cAMPdependent signalling pathway has been shown [3±7] to depend on expression of specific receptors for glucagon-like peptide-1-(7±36) amide (GLP-1), glucosedependent insulinotropic polypeptide (GIP) and glucagon. The gastrointestinal hormones GLP-1 and GIP effectively increase glucose-induced insulin release in vitro [8±10]; their pivotal role as incretin hormones has been recently illustrated in two mouse models with homozygous null mutations in the respective genes [11,12]. It is not clear whether similar mechanisms operate in human beta cells. More than three decades ago insulin release in humans was shown to be dually stimulated by glucose and glucagon [13,14], the glucagon effect appearing independent of enhanced glucose mobilisation from the liver ]-glucagon-amide (n = 8; p < 0.05), indicating participation of endogenously released glucagon in the process of glucose-induced insulin release. The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon. Conclusion/interpretation. These data suggest that human beta cells express functional glucagon receptors which can, similar to incretin hormone receptors, generate synergistic signals for glucose-induced insulin secretion.

show abstract

“…Cloning of the human (Lok et al, 1994;MacNeil et al, 1994;Menzel et al, 1994) and mouse receptor genes (Burcelin et al, 1995) followed. The human glucagon receptor gene is localized to chromosome 17, at 17q25 (Lok et al, 1994;Menzel et al, 1994). The rat and mouse glucagon receptors are 485-amino acid seven transmembrane domain proteins with four N-linked glycosylation sites and a sequence motif in the third intracellular loop (RLAR) known to be required for G protein activation.…”

Section: Gene Structure and Expressionmentioning

confidence: 99%

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

et al. 2003

View full text Add to dashboard Cite

The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization

Cited by 115 publications

References 23 publications

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

Glucagon receptors on human islet cells contribute to glucose competence of insulin release

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

Contact Info

Product

Resources

About