Homozygous P86S Mutation of the Human Glucagon Receptor Is Associated With Hyperglucagonemia, α Cell Hyperplasia, and Islet Cell Tumor

Zhou, Cuiqi; Dhall, Deepti; Nissen, Nicholas N.; Chen, Chun-Rong; Yu, Run

doi:10.1097/mpa.0b013e3181b2bb03

Cited by 134 publications

(111 citation statements)

References 21 publications

(38 reference statements)

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“…This finding raises the interesting possibility of an increased recruitment of GCG-expressing cells in the pancreatectomized patients as a response to the removal of the pancreatic a-cells. In line with this, pancreatic a-cell hyperplasia is observed in total disruption of glucagon receptor signaling in mice (46,47) and during partial disruption of glucagon receptor signaling in humans (48). Furthermore, studies in mice with complete disruption of glucagon receptor signaling specifically in the liver have pointed to the existence of a circulating factor, which stimulates a-cell proliferation when glucagon signaling is abolished (49,50).…”

Section: Discussionmentioning

confidence: 49%

Evidence of Extrapancreatic Glucagon Secretion in Man

et al. 2015

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Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from a-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.Patients with diabetes are characterized not only by compromised insulin secretion and action but also by elevated plasma concentrations of the 29-amino acid peptide hormone glucagon, which hitherto has been considered a pancreas-derived hormone in humans (produced in and secreted from a-cells in the islet of Langerhans) (1). In patients with diabetes, plasma concentrations of glucagon are elevated in the fasting state and fail to decrease appropriately or even increase in response to an oral glucose tolerance test (OGTT) and show exaggerated increases in response to ingestion of a mixed meal (1,2). The elevated glucagon concentrations increase the hepatic glucose production and thereby contribute significantly to the fasting and postprandial hyperglycemia characterizing patients with diabetes. The etiology behind diabetic hyperglucagonemia is still controversial. Whereas oral intake of glucose elicits a hyperglucagonemic response, intravenous glucose administration causes suppression of plasma glucagon levels (3,4). A "lighter version" of this phenomenon has also been observed in healthy individuals after ingestion of larger oral glucose loads (4). Together, these findings led us to speculate that postprandial hyperglucagonemia could be gut derived and independent of the endocrine pancreas.The notion of extrapancreatic glucagon secretion in man has been debated for years, and several studies looking at glucagon responses after total pancreatectomy in animals (5-10) and man (11-24) have been published. Overall, these investigations have reported very conflicting

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Section: Discussionmentioning

confidence: 49%

Evidence of Extrapancreatic Glucagon Secretion in Man

et al. 2015

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“…Three groups of mutant proteins stood out. The first group of mutations included Trp-36, Asp-63, and Pro-86, which were previously identified as glucagon binding residues in a structure model of the full-length glucagon-GCGR complex (12), and their mutations abrogated glucagon binding (12,21). The corresponding fusion proteins were expressed at levels comparable with those of the wild type fusion protein (Fig.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Zhao

Yin

Yang

et al. 2016

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF 1 R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation.The class B or secretin family of GPCRs consists of 15 receptors for peptide hormones that include glucagon, glucagon-like peptides, parathyroid hormone, and calcitonin (Fig. 1A). These receptors are important drug targets for many human diseases including diabetes, neurodegeneration, cardiovascular diseases, and psychiatric disorders. The full-length receptors consist of two modular domains: a globular extracellular domain (ECD) 3 defined by three conserved disulfide bonds and a TMD that contains seven transmembrane helices (1-4). The ECD is responsible for the high affinity and specificity of hormone binding, and the TMD is required for receptor activation and signal coupling to downstream G proteins and other signaling effectors (4). Peptide hormone binding is thought to proceed through fast binding of its C terminus to the ECD followed by a slower association of the peptide N terminus with the receptor TMD (5), which leads to conformational changes in the receptor TMD and the receptor activation. The activated receptors are coupled primarily to stimulatory G proteins, resulting in elevation of the intracellular cAMP level.Structures of the ECDs of class B GPCRs in complex with their peptide ligands have been determined by x-ray crystallography (1, 6 -9) and NMR (10) and have provided useful information about structural mechanisms of ligand recognition and selectivity (2, 11). Only recently, crystal structures of t...

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“…A cluster of invariant or conserved residues forms a shallow cleft at the interface of αA, L2-L5, and αC and, according to studies of loss of function mutations in this region, this cleft is expected to form the binding site for the glucagon peptide. An individual homozygous for a P86S mutation has hallmarks of loss of glucagon action, and this receptor variant was unable to bind glucagon in vitro (10). Residues at the base of L4 adjacent to P86, including the invariant P82 and conserved Y84 and L85, form part of an extended hydrophobic surface in the canonical hormone-binding pocket (16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Antagonist and Inverse Agonist Antibodies Targeting The Gcgrmentioning

confidence: 99%

“…Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3)(4)(5)(6)(7)(8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4,(9)(10)(11)(12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR. The current model for activation class B GPCRs proposes a tethering mechanism whereby the C-terminal half of the peptide ligand first binds a large extracellular domain (ECD), thereby enabling a high-affinity interaction of the N-terminal half of the ligand with a cleft formed by the transmembrane α-helical bundle (13,14), termed the juxtamembrane (JM) domain.…”

mentioning

confidence: 99%

Molecular basis for negative regulation of the glucagon receptor

Koth¹,

Murray²,

Mukund³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

179

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Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.T he glucagon receptor (GCGR) is a member of the class B G protein-coupled receptor (GPCR) family (1) that mediates the activity of glucagon, a pancreatic islet-derived peptide hormone that plays a central role in the pathophysiology of diabetes (2). Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3-8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4, 9-12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR. The current model for activation class B GPCRs proposes a tethering mechanism whereby the C-terminal half of the peptide ligand first binds a large extracellular domain (ECD), thereby enabling a high-affinity interaction of the N-terminal half of the ligand with a cleft formed by the transmembrane α-helical bundle (13,14), termed the juxtamembrane (JM) domain. This interaction induces a structural change in the transmembrane and intracellular face of the receptor that enables G protein coupling, likely similar to that described for the activated form of the β-adrenergic receptor (15). Recent structural studies of several class B GPCR ECDs and ECD-ligand complexes support this model (16)(17)(18)(19)(20)(21). Glucagon likely interacts with GCGR in a similar fashion to the interaction of other peptide ligands with class B GPC...

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Homozygous P86S Mutation of the Human Glucagon Receptor Is Associated With Hyperglucagonemia, α Cell Hyperplasia, and Islet Cell Tumor

Cited by 134 publications

References 21 publications

Evidence of Extrapancreatic Glucagon Secretion in Man

Evidence of Extrapancreatic Glucagon Secretion in Man

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Molecular basis for negative regulation of the glucagon receptor

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