In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor

Bazarsuren, A.; Grauschopf, Ulla; Wozny, Manfred; Reusch, Dietmar; Hoffmann, Eike; Schaefer, W.; Panzner, Steffen; Rudolph, Rainer

doi:10.1016/s0301-4622(02)00023-6

Cited by 76 publications

(103 citation statements)

References 39 publications

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“…Together these studies have formulated a picture of how GLP-1 and Ex-4 bind to this receptor and what regions of GLP-1R are important for agonist recognition. The isolated N-terminus of the rat (Lopez de Maturana et al, 2003;Wilmen et al, 1996;Xiao et al, 2000) and human (Bazarsuren et al, 2002) GLP-1R associate with GLP-1, although with lower affinity than with the native receptor (Bazarsuren et al, 2002;Xiao et al, 2000). Similar to the glucagon receptor and other members of this subfamily, GLP-1R has six cysteine residues in the extracellular region that are highly conserved (Thorens et al, 1993).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

“…Similar to the glucagon receptor and other members of this subfamily, GLP-1R has six cysteine residues in the extracellular region that are highly conserved (Thorens et al, 1993). Disulphide bonds occur between cysteines 46 and 71, 62 and 104, 85 and 126 of human GLP-1R (Bazarsuren et al, 2002). Denaturation of the isolated Nterminal receptor fragment of the rat (Wilmen et al, 1996) or human (Bazarsuren et al, 2002) receptor results in complete loss of affinity for the native peptide.…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

“…Disulphide bonds occur between cysteines 46 and 71, 62 and 104, 85 and 126 of human GLP-1R (Bazarsuren et al, 2002). Denaturation of the isolated Nterminal receptor fragment of the rat (Wilmen et al, 1996) or human (Bazarsuren et al, 2002) receptor results in complete loss of affinity for the native peptide. Deletion of portions of the N-terminal of the rat GLP-1R or substitution of amino acids 1-134 with the equivalent sequence of the glucagon receptor eliminates affinity for GLP-1 (Graziano et al, 1996).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

583

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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Section: Glp-1r In the Pancreasmentioning

confidence: 99%

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

583

465

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“…Family B GPCRs are characterized by an N-terminal domain of ϳ100 -150 amino acids containing 6 conserved cysteine residues. The disulfide bonding patterns of these conserved cysteine residues have been determined in three different receptor types and are equivalent, suggesting that this domain forms a related fold in all Family B GPCRs (23)(24)(25)(26).…”

Section: ) For Example In 1964mentioning

confidence: 99%

“…Although other regions of the receptor are also involved (e.g. 21,29,30), GLP-1 clearly also interacts directly with the N-terminal domain of its receptor (26,28,29). The isolated N-terminal domain of GLP-1R has been expressed in several systems.…”

Section: ) For Example In 1964mentioning

confidence: 99%

The Isolated N-terminal Domain of the Glucagon-like Peptide-1 (GLP-1) Receptor Binds Exendin Peptides with Much Higher Affinity than GLP-1

Maturana

Willshaw

Kuntzsch

et al. 2003

Journal of Biological Chemistry

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It is well known that the action of glucose on pancreatic islets results in increased plasma insulin levels. Nevertheless, high blood glucose levels are not solely responsible for increased insulin secretion (for review, see Ref. 1). For example, in 1964 McIntyre et al. (2) demonstrated that intravenous injection of glucose resulted in a smaller insulin release than that resulting from intrajejunal glucose injection, even though the latter produced lower blood glucose levels compared with the former. Hence, glucose-dependent insulin secretion requires a nutrientdependent component, which was believed to be an endocrine transmitter termed an "incretin" (3). It has since been demonstrated that two hormones, glucagon-like peptide-1 and glucosedependent insulinotropic polypeptide, are responsible for the incretin effect (1).The predominant active form of GLP-1 is actually glucagonlike peptide-1(7-36)amide (termed GLP-1 1 throughout this paper), a 30-residue peptide hormone derived from the post-translational modification of proglucagon in intestinal L cells (1). GLP-1 not only increases glucose-dependent insulin secretion (4 -6), but it also decreases glucose-dependent glucagon secretion (7, 8) and decelerates gastric emptying (9). In addition, GLP-1 has been shown to reduce appetite in rats (10) and to stimulate proinsulin gene transcription and biosynthesis in pancreatic ␤-cells (11, 12). The physiological roles of GLP-1 in maintaining blood sugar levels, via a glucose-dependent mechanism, have heightened interest in the GLP-1 receptor (GLP-1R) as a target for glucose-dependent therapeutic agents designed to treat hyperglycemia resulting from diabetes (13,14). Unfortunately, the half-life of GLP-1 itself after subcutaneous injection is very short because of dipeptidyl peptidase IV cleavage of the first 2 N-terminal residues (15), and so future research requires the design of physiologically stable GLP-1R agonists.The venom of the Gila monster Heloderma suspectum contains a mixture of compounds that includes several peptides related in sequence to GLP-1. Two of these, exendin-3 and exendin-4, are 39-amino acid peptides that share ϳ50% sequence identity to GLP-1 itself and are indeed potent GLP-1R agonists (Fig. 1) (16, 17). Interestingly, although GLP-1 affinity is highly sensitive to N-terminal cleavage, exendin-4 can be truncated by up to 8 residues at its N terminus without significant loss of affinity, suggesting that relative to GLP-1, the central and/or C-terminal residues form additional stabilizing contacts with the receptor (15, 18). Nevertheless, the first two amino acids are also essential for the efficacy of exendin peptides because, once removed, the truncated exendin peptides function as antagonists or inverse agonists (16 -19).

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Introduction to Membrane Proteins

Chiu

2002

CP Protein Science

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In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor

Cited by 76 publications

References 39 publications

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

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

The Isolated N-terminal Domain of the Glucagon-like Peptide-1 (GLP-1) Receptor Binds Exendin Peptides with Much Higher Affinity than GLP-1

Introduction to Membrane Proteins

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