Scanning of the Glucagon-Like Peptide-1 Receptor Localizes G Protein-Activating Determinants Primarily to the N Terminus of the Third Intracellular Loop

Mathi, Swarna K.; Chan, Yvonne; Li, Xinfang; Wheeler, Michael B.

doi:10.1210/mend.11.4.9913

Cited by 54 publications

(38 citation statements)

References 28 publications

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“…It may therefore be concluded that the basic residues forming the BBXB motif in the i1 loop of the ␣ 1b -AR do not play a significant role in receptor-G protein coupling. These findings are in agreement with those from other studies on various GPCRs indicating that amino acids in the i1 loop are not important (22,23) or only play a modest role (24,25) in receptor-G protein coupling. (Table I).…”

Section: Mutagenesis Of Basic Residues In the I1supporting

confidence: 93%

Mutational and Computational Analysis of the α1b-Adrenergic Receptor

Greasley¹,

Fanelli²,

Scheer³

et al. 2001

Journal of Biological Chemistry

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To investigate their role in receptor coupling to G q , we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the ␣ 1b -adrenergic receptor (AR) GPCRs are structurally characterized by seven transmembrane ␣-helices connected by alternating extracellular (e) and intracellular (i) loops. While the extracellular portion of these receptors is primarily involved in ligand binding, the cytosolic loops mediate the interaction of the receptors with a number of signaling and regulatory proteins, including G proteins, arrestins, and G protein-coupled receptor kinases (reviewed in Ref..2).Evidence suggests that a conformational adjustment within the helical bundle of the receptor underlies the process of agonist-induced activation of GPCRs (reviewed in Ref.3). The current hypothesis is that the transition from the inactive (R) to active (R*) state of a GPCR results in receptor interaction with, and activation of, a G protein. Thus a GPCR-mediated biological response involves a series of events (i.e. receptor activation, receptor-G protein interaction, and receptor-induced G protein activation) for which a detailed mechanism still remains elusive at the molecular level. Although residues located in the helical bundle and at the boundary between the membrane and the cytosol may play a role in the "conformational switch" underlying receptor activation, amino acids in the intracellular loops are believed to be more directly involved in receptor-G protein interaction and/or receptor-induced G protein activation. The combination of these two latter events, which cannot be unequivocally separated experimentally, is generally indicated with the term of receptor-G protein coupling.We have previously provided evidence that the negatively and positively charged amino acids of the conserved DRY motif at the cytosolic end of helix 3 play a key role in the activation process of the ␣ 1b -AR (4 -6). Following a combination of experimental and computer-simulated mutagenesis of the ␣ 1b -AR, we have hypothesized that protonation of the aspartate (Asp 142 ) and a shift of the arginine (Arg 143 ) out of a conserved "polar pocket" are crucial steps in the transition of the receptor from the inactive (R) to active (R*) state (4 -6).Several studies have tried to identify the amino acids of different GPCRs involved in G protein coupling at both experimental (as reviewed in Ref.2) and theoretical levels (7-10). The majority of these studies indicate that sequences in the i2 loop as well as in the N and C termini of the i3 loop play an

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Section: Mutagenesis Of Basic Residues In the I1supporting

confidence: 93%

Mutational and Computational Analysis of the α1b-Adrenergic Receptor

Greasley¹,

Fanelli²,

Scheer³

et al. 2001

Journal of Biological Chemistry

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“…A following report focusing on point mutations in the N-terminal region of IC 3 proximal to the TM 5 i.e. the region F 321 to L 339 revealed the importance of residues V 327 , I 328 and V 331 in cAMP stimulation (Mathi et al, 1997). Based on a comparison with a similar region (IC 3 /TM 5 junction) in the M 5 muscarinic receptor, Wheeler and colleagues hypothesized that the residues, V 327 , I 328 , V 331 and K 334 form the hydrophobic face of an α-helical structure and as such would be directly associated with the G-protein.…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

“…Some residues in the IC 1 /TM 2 region of the rat GLP-1R have also been found to be of importance in cAMP production. These include H 180 and R 176 (Mathi et al, 1997) although only the latter was associated with an exclusive decrease in cAMP production independent of a loss of affinity of the mutated receptor for GLP-1.…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

556

445

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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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“…ICL1 and ICL3 specifically mediate Gαs whereas ICL2 activates Gαs, Gαi/o and Gαq/11 [134]. An alanine substitution at Arg 176 within ICL1, caused a reduction in GLP-1 mediated stimulation of cAMP but had no effect on receptor expression or internalisation ( Figure 6) [198]. Additionally, different domains of ICL3 have been shown to be responsible for the Gαs and Gαi/o activation.…”

Section: Icls Ecls and Tm Domains Of The Glp-1rmentioning

confidence: 99%

“…, where TM5 meets ICL3, caused significantly lowered cAMP production but had no effect on receptor expression ( Figure 6). These residues and Lys 334 form a hydrophobic face that interacts directly with the G-protein [198]. A single block deletion of Lys 334 -Leu 335 -Lys 336 within the N-terminal half of ICL3 caused a significant decrease in cAMP production in response to GLP-1, of which Lys 334 showed most significance with no effect on receptor expression ( Figure 6).…”

Section: Icls Ecls and Tm Domains Of The Glp-1rmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Thompson¹

2013

Clin Exp Pharmacol

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It has been estimated that approximately 8.4% of the world population currently live with diabetes mellitus and type 2 diabetes is the most common form. Type 2 diabetes increases the risk of complications such as heart attacks, blindness, amputations and kidney failure. Glucagon like Peptide-1 (GLP-1) is an effective insulinotropic agent and therefore its effects on insulin secretion have been greatly examined for more than two decades. It is a polypeptide hormone secreted by the intestinal L-cells into the blood in response to food uptake. GLP-1 has a very short half-life in vivo due to the rapid proteolytic degradation by Dipeptidyl Peptidase IV (DPP-IV). Therefore DPP-IV resistant GLP-1 analogues, Exenatide and Liraglutide, have been developed and are currently being used in the treatment of type 2 diabetes. GLP-1 agonist functions by binding to its receptor, GLP1R, on the cell surface.The GLP-1R belongs to the class B peptide receptor family based on its structure and function. The binding of GLP-1 to its receptor results in activation of Gαs coupled adenylyl cyclase and the production of cyclic Adenosine Monophosphate (cAMP), which enhances glucose-induced insulin secretion. Continuous GLP-1R activation also causes insulin secretion and pancreatic islet β-cell proliferation and neogenesis. The GLP-1R is internalised following its activation, which regulates the biological responsiveness of the receptor. Structurally the GLP-1R contains a large N-terminal extracellular domain (TM1-TM7) joined by three intracellular loops (ICL1, ICL2, ICL3) and three extracellular loops (ECL1, ECL2, ECL3), and an intracellular C-terminal domain. These domains play critical roles in GLP-1R trafficking to the cell surface, and also in agonist dependent activation and internalisation of the receptor. This review is focused on type 2 diabetes, its treatment with GLP-1, GLP-1R structure and function, and the physiological affects resulting from GLP-1R activation.

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Scanning of the Glucagon-Like Peptide-1 Receptor Localizes G Protein-Activating Determinants Primarily to the N Terminus of the Third Intracellular Loop

Cited by 54 publications

References 28 publications

Mutational and Computational Analysis of the α1b-Adrenergic Receptor

Mutational and Computational Analysis of the α1b-Adrenergic Receptor

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

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

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