Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population

Tokuyama, Yoshiharu; Matsui, Kana; Egashira, Toru; Nozaki, Osamu; Ishizuka, Toshiharu; Kanatsuka, Azuma

doi:10.1016/j.diabres.2004.02.004

Cited by 64 publications

(64 citation statements)

References 24 publications

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“…Of note, this residue was in the same region as the receptor residues Glu 125 and Glu 133 that were labeled by carboxyl-terminal Bpa 35 and Bpa 24 GLP1 probes, respectively (27). This Tyr 145 residue is adjacent to a functionally important residue, Thr 149 of the GLP1 receptor, in which a T149M mutation was found in a type 2 diabetes patient that exhibited impairment of insulin secretion, insulin sensitivity, and glucose tolerance (41). This mutant has been shown to exhibit reduced binding affinity and biological activity efficacy for GLP1 in COS-7 cells (42).…”

Section: Discussionmentioning

confidence: 99%

Spatial Approximations between Residues 6 and 12 in the Amino-terminal Region of Glucagon-like Peptide 1 and Its Receptor

Chen

Pinon

Miller

et al. 2010

Journal of Biological Chemistry

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Understanding the molecular basis of natural ligand binding and activation of the glucagon-like peptide 1 (GLP1) receptor may facilitate the development of agonist drugs useful for the management of type 2 diabetes mellitus. We previously reported molecular approximations between carboxyl-terminal residues 24 and 35 within GLP1 and its receptor. In this work, we have focused on the amino-terminal region of GLP1, known to be critical for receptor activation. We developed two high-affinity, full agonist photolabile GLP1 probes having sites of covalent attachment in positions 6 and 12 of the 30-residue peptide (GLP1(7-36)). Both probes bound to the receptor specifically and covalently labeled single distinct sites. Glucagon-like peptide 1 (GLP1), 2 secreted by the intestinal L cells in response to food ingestion, is a glucoincretin hormone that possesses multiple physiological functions, including stimulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction in food intake, augmenting insulin biosynthesis, restoring ␤-cell sensitivity to glucose, increasing ␤-cell proliferation, and reducing apoptosis (1, 2). Because of these multiple antidiabetic actions and its ability to lower body weight, GLP1 receptor agonists have attracted much interest as a treatment for type 2 diabetes (3).The GLP1 receptor is a member of the family B G proteincoupled receptors (GPCRs) that includes many important drug targets such as receptors for glucagon, glucagon-like peptide 2, gastric inhibitory polypeptide, secretin, vasoactive intestinal polypeptide, corticotropin-releasing factor, parathyroid hormone and calcitonin (4). A signature structural feature of this family is a long and structurally complex extracellular aminoterminal domain containing six conserved cysteine residues that form disulfide bonds that contribute to the development of a highly folded structure (5-9). This domain has been suggested to be the predominant domain for natural ligand binding and this is a consistent theme throughout the family (10 -16). Natural ligands for family B receptors are all moderately long peptides in excess of 25 residues that have diffuse pharmacophoric domains, contributing to the complexity of their flexible interactions with the receptor amino-terminal domain. Like natural ligands for other members in the family B GPCRs, the aminoterminal portion of GLP1 is critical for the receptor selectivity and activation, whereas the carboxyl-terminal portion is critical for high affinity ligand binding (17). A tethering mechanism involving two domains of binding, with the carboxyl-terminal region of the ligand binding to the receptor amino terminus, and the amino-terminal region of the ligand possibly interacting with the receptor body, has been proposed for activation of this family of receptors (18 -20).Recently, our understanding of the molecular basis of ligand binding of the family B GPCRs has been substantially advanced with the solution of the NMR and crystal structures of the amin...

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Section: Discussionmentioning

confidence: 99%

Spatial Approximations between Residues 6 and 12 in the Amino-terminal Region of Glucagon-like Peptide 1 and Its Receptor

Chen

Pinon

Miller

et al. 2010

Journal of Biological Chemistry

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“…GLP-1R is a 64 kDa protein (Widmann et al, 1995) and although alternate splicing results in two different transcripts for both the rat and the human GLP-1R Thorens, 1992) there has, as yet, been only one functionally distinct GLP-1R described. While various polymorphisms have been associated with the GLP-1R human gene locus (Stoffel et al, 1993), linkage analysis eliminates an association with the majority of T2DM cases, based on the populations studied (Tanizawa et al, 1994;Tokuyama et al, 2004;Yagi et al, 1996;Zhang et al, 1994). One patient diagnosed with T2DM from a Japanese study (Tokuyama et al, 2004) exhibited impairment of insulin secretion, insulin sensitivity and glucose tolerance and had a missense mutation resulting in substitution of threonine 149 with methionine (T149M).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

“…While various polymorphisms have been associated with the GLP-1R human gene locus (Stoffel et al, 1993), linkage analysis eliminates an association with the majority of T2DM cases, based on the populations studied (Tanizawa et al, 1994;Tokuyama et al, 2004;Yagi et al, 1996;Zhang et al, 1994). One patient diagnosed with T2DM from a Japanese study (Tokuyama et al, 2004) exhibited impairment of insulin secretion, insulin sensitivity and glucose tolerance and had a missense mutation resulting in substitution of threonine 149 with methionine (T149M). The mutated receptor exhibited a reduced affinity in vitro for GLP-1 and Ex-4 (Beinborn et al, 2005).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

576

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…Although SNPs have been characterized in great detail for many G protein-coupled receptors, there is limited knowledge on the effects of SNPs at the GLP-1R. Several GLP-1R SNPs have been assessed previously in vitro, although not explored in a wide range of functional outputs (Beinborn et al, 2005;Fortin et al, 2010) and at least one has been reported to have a loose association with type II diabetes mellitus (Tokuyama et al, 2004). A better understanding of the role of these polymorphisms in receptor function is therefore required, not only to gain an insight into the effects they have on receptor function but also to understand their possible association with the onset of disease or effectiveness of drug therapies.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

Koole¹,

Wootten²,

Simms³

et al. 2011

Mol Pharmacol

117

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The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can exist in an amidated form (GLP-1(1-36)NH 2 and GLP-1(7-36)NH 2 ) and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms (SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellular signal-regulated kinase 1/2 phosphorylation, and intracellular Ca 2ϩ mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligandand pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the Met 149 receptor variant. At the Met 149 variant, there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the Cys 333 variant, peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the Met 149 receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.

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Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population

Cited by 64 publications

References 24 publications

Spatial Approximations between Residues 6 and 12 in the Amino-terminal Region of Glucagon-like Peptide 1 and Its Receptor

Spatial Approximations between Residues 6 and 12 in the Amino-terminal Region of Glucagon-like Peptide 1 and Its Receptor

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Polymorphism and Ligand Dependent Changes in Human Glucagon-Like Peptide-1 Receptor (GLP-1R) Function: Allosteric Rescue of Loss of Function Mutation

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