Disease relevance of GCGR

• We conclude that the Gly40Ser polymorphism of the GCGR gene is associated with higher risk of hypertension and with enhanced proximal tubular sodium reabsorption, a factor possibly contributing to hypertension in this group [1].
• An Alu-repeat poly(A) polymorphism colocalized to GCGR was used in the present study to test for association and linkage in hypertension as well as association in obesity development [2].
• Characterization of the glucagon receptor in a pheochromocytoma [3].
• A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus [4].
• A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus [5].

High impact information on GCGR

• Glucagon receptor gene mutation in essential hypertension [6].
• We report the association of a single heterozygous Gly to Ser missense mutation in the glucagon receptor gene with late-onset NIDDM [4].
• We assessed the impact of low blood glucose on the vision of C57BL/6J mice rendered hypoglycemic by a null mutation of the glucagon receptor gene, Gcgr [7].
• Mutation of the glucagon receptor gene and diabetes mellitus in the UK: association or founder effect [8]?
• Design of a Long Acting Peptide Functioning as Both a Glucagon-like Peptide-1 Receptor Agonist and a Glucagon Receptor Antagonist [9].

Chemical compound and disease context of GCGR

• Hypothesis: glucagon receptor glycine to serine missense mutation contributes to one in 20 cases of essential hypertension [10].
• A possible pathogenic mutation in the glucagon receptor gene causing a Gly to Ser change at codon 40 (Gly40Ser) was reported to be associated and linked with non-insulin-dependent diabetes mellitus (NIDDM), in France and Sardinia [5].
• The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia [11].

Biological context of GCGR

• The gene encoding the human glucagon receptor (GCGR) was mapped to chromosome band 17q25 by fluorescence in situ hybridization to metaphase chromosomes [12].
• Quantitative autoradiography demonstrated the presence of abundant [(125)I-Thyr(10)]glucagon binding sites in pheochromocytomas, which were displaced by both cold glucagon and the glucagon receptor antagonist Des-His(1)[Glu(9)]glucagon amide (GR-A) [13].
• Localization of the glucagon receptor gene to human chromosome band 17q25 [12].
• A cDNA encoding a complete functional human glucagon receptor (GGR) was isolated from a liver cDNA library by a combination of polymerase chain reaction and colony hybridization [14].
• Transfection of the human glucagon receptor into COS-7 cells confers upon them high affinity binding for [125I] glucagon [15].

Anatomical context of GCGR

• Glucagon-receptor mRNA was detected by reverse transcription-polymerase chain reaction in three human pheochromocytomas, but not in four normal adrenal medullas [13].
• We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes [11].
• Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1) [11].
• Following administration of a saturating dose of glucagon to rats, a rapid internalization of glucagon receptor was observed coincident with its serine phosphorylation both at the plasma membrane and within endosomes [16].
• Monkey glucagon receptor was expressed in CHO cells, either with (mkGCGR) or without (mkGCGRDelta14) the 14-amino acid C-terminal extension to approximate the human receptor [17].

Associations of GCGR with chemical compounds

• The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia [18].
• Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively) [19].
• One major difference was observed between the glucagon receptor in tumor tissue and that in liver and heart, namely, a marked lability in 125-I-glucagon binding and adenylate cyclase activity [3].
• The cDNA encodes a receptor protein with 80% identity to rat GGR that binds [125I]glucagon and transduces a signal leading to increases in the concentration of intracellular cyclic adenosine 3',5'-monophosphate [14].
• The glucagon receptor was functionally coupled to increases in cyclic AMP in S2 cells [20].

Physical interactions of GCGR

• In addition, the glucagon receptor core domain (7TM helices and connecting loops) strongly determines specificity for the glucagon amino terminus [21].

Enzymatic interactions of GCGR

• Therefore, these results reveal that within hepatic target cells and consequent to glucagon-mediated internalization of the serine-phosphorylated glucagon receptor and the Gsalpha protein, extended signal transduction may occur in vivo at the locus of the endo-lysosomal apparatus [16].

Regulatory relationships of GCGR

• The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon [22].

Other interactions of GCGR

• Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus [21].
• Substitution of distinct segments of the glucagon receptor core domain with the corresponding segments of the GLP-1 receptor rescued the affinity and potency of specific glucagon analogs [21].
• Another chimeric receptor (NtGGr) with the N-terminal domain of the glucagon receptor spliced onto the C-terminal regions of the CT receptor shows no high affinity binding of sCT [23].
• The glucagon receptor is a member of the G protein-coupled receptor superfamily [24].
• New approaches with mechanisms different from current therapies are being explored, including novel ligands of peroxisome proliferator-activated receptor, glucagon receptor antagonists, dipeptidyl peptidase IV inhibitors, and insulin receptor activators [25].

Analytical, diagnostic and therapeutic context of GCGR

• Site-directed mutagenesis identified the Asp385 --> Glu glucagon receptor mutant that specifically rescued Ala2-glucagon [21].
• Southern blot analysis of human DNA reveals a hybridization pattern consistent with a single GGR locus [14].
• From this point of view, the extracellular fragment of human glucagon receptor used in this study seems to be a new potent ligand for fusion protein-based affinity chromatography [26].
• Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells [27].
• A linkage and cross-sectional study of hypertension and obesity using a poly (A) Alu-repeat polymorphism at the glucagon receptor gene locus (17q25) [2].

References