The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: May 10, 2021

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled (GPCR) which mediates the effects of GLP-1, an incretin hormone secreted primarily from L-cells in intestine and within central nervous system. GLP-1R, upon activation, exerts several metabolic including release insulin suppression appetite, has, accordingly, become important target for treatment type 2 diabetes (T2D). Recently, there has been heightened interest how activated GLP-1R trafficked between different endomembrane compartments, controlling spatial origin duration intracellular signals. discovery “biased” agonists that show altered trafficking profiles selective engagement with effectors added to tools available study mechanisms physiological importance these processes. In this review we survey early recent work shed light on interplay signalling trafficking, it might be therapeutically tractable T2D related diseases.

Language: Английский

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Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells

Endocrinology, Journal Year: 2023, Volume and Issue: 164(5)

Published: Feb. 12, 2023

Abstract The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR), are prime therapeutic targets for the treatment of type 2 diabetes (T2D) obesity. They expressed in pancreatic beta cells where they potentiate insulin release response to food intake. Despite GIP being main healthy individuals, GLP-1R has been favored as a target due blunted GIPR responses T2D patients conflicting effects agonists antagonists improving glucose tolerance preventing weight gain. There is, however, recently renewed interest biology, following realization that can be restored after an initial period blood normalization recent development dual GLP-1R/GIPR with superior capacity controlling levels weight. importance trafficking subcellular signaling control outputs is well established, but little known about pattern spatiotemporal from cells. Here, we have directly compared surface expression, trafficking, characteristics both receptors identify potential differences might underlie distinct pharmacological associated each receptor. Our results indicate increased cell levels, internalization, degradation, endosomal vs plasma membrane activity GLP-1R, while instead recycling, reduced desensitization, enhanced downstream signal amplification. These implications function.

Language: Английский

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The therapeutic potential of GLP‐1 receptor biased agonism

British Journal of Pharmacology, Journal Year: 2021, Volume and Issue: 179(4), P. 492 - 510

Published: April 21, 2021

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes as they stimulate insulin release and promote weight loss through appetite suppression. Their main side effect is nausea. All approved GLP-1 full across multiple signalling pathways. However, selective engagement with specific intracellular effectors, or biased agonism, has been touted a means to improve therapeutic efficacy. In this review, I critically examine how receptor-mediated linked physiological responses discuss the implications of recent studies investigating metabolic effects agonists. Overall, there little conclusive evidence that beneficial adverse attributable distinct, nonoverlapping Instead, G protein-biased appear achieve enhanced anti-hyperglycaemic efficacy by avoiding desensitisation downregulation, partly via reduced β-arrestin recruitment. This seemingly applies more than regulation nausea, possible reasons which discussed. At present, most derives from cellular animal studies, human data required determine whether approach represents genuine advance. LINKED ARTICLES: article part themed issue on GLP1 ligands (BJP 75th Anniversary). To view other articles in section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Language: Английский

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Glucagon Like Peptide 1 Receptor Agonists for Targeted Delivery of Antisense Oligonucleotides to Pancreatic Beta Cell

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(9), P. 3416 - 3429

Published: Feb. 24, 2021

The extra hepatic delivery of antisense oligonucleotides (ASOs) remains a challenge and hampers the widespread application this powerful class therapeutic agents. In that regard, pancreatic beta cells are particularly attractive but challenging cell type because their pivotal role in diabetes fact they refractory to uptake unconjugated ASOs. To circumvent this, we have expanded our understanding structure activity relationship ASOs conjugated Glucagon Like Peptide 1 Receptor (GLP1R) agonist peptide ligands. We demonstrate key linker chemistry its optimization design maleimide based conjugates with improved vivo efficacy. addition, truncation studies scoping diverse set GLP1R agonists proved fruitful identify additional targeting ligands efficacious including native hGLP1(7–36)NH2. Variation carrier also shed some light on dramatic impact subtle sequence differences corresponding ASO conjugate performance vivo, an area which clearly warrant further investigations. confirmed remarkable potential conjugation for by effectively knocking down islet amyloid polypeptide (IAPP) mRNA, proapoptotic target, mice.

Language: Английский

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Biased agonism and polymorphic variation at the GLP-1 receptor: Implications for the development of personalised therapeutics

Pharmacological Research, Journal Year: 2022, Volume and Issue: 184, P. 106411 - 106411

Published: Aug. 22, 2022

Glucagon-like peptide-1 receptor (GLP-1R) is a well-studied incretin hormone and target of several therapeutic drugs for type 2 diabetes (T2D), obesity and, more recently, cardiovascular disease. Some signalling pathways downstream GLP-1R may be responsible drug adverse effects such as nausea, while others mediate outcomes incretin-based T2D therapeutics. Understanding the interplay between different factors that alter signalling, trafficking, activity, including biased agonism, single nucleotide polymorphisms structural modifications key to develop next-generation personalised agonists. However, these interactions remain poorly described, especially novel therapeutics dual tri-agonists than one receptor. Comparison structures in complex with G proteins peptide non-peptide agonists has revealed insights into important agonist-residue networks crucial activation, recruitment engagement specific pathways. Here, we review latest knowledge on structure providing evidence agonism delineating associated this phenomenon. We survey current multi-agonists at stages development, highlighting possible challenges their translational potential. Lastly, discuss findings related non-synonymous genomic variants GLP1R functional importance residues involved function. propose studies polymorphisms, specifically effect dynamics pharmacology response agonists, could have significant impact precision medicine approaches development

Language: Английский

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GLP-1R Signaling and Functional Molecules in Incretin Therapy

Molecules, Journal Year: 2023, Volume and Issue: 28(2), P. 751 - 751

Published: Jan. 11, 2023

Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting have entered clinical treatment. However, novel functional molecules with reduced side effects enhanced efficacy are still in high demand. In this review, we summarize the basis of signaling, how it involved treatment T2DM. We review incretin therapy various stages trials. also outline current strategies emerging techniques that furthering development T2DM other metabolic diseases.

Language: Английский

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Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell–specific β-arrestin 2 knockout mice

Science Advances, Journal Year: 2023, Volume and Issue: 9(18)

Published: May 3, 2023

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 adult β cell-specific β-arrestin knockout (KO) mice. KOs displayed sex-dimorphic phenotype consisting of weaker acute improved 6 hours after injection. Similar effects were observed for semaglutide and tirzepatide with biased exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases impaired, desensitization reduced KO islets. former defect was attributed enhanced 1 phosphodiesterase 4 activities, while co-occurred impaired recycling lysosomal targeting, increased trans-Golgi network signaling, ubiquitination. This study has unveiled fundamental aspects response regulation direct application rational design GLP-1R-targeting therapeutics.

Language: Английский

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Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling

Science Signaling, Journal Year: 2024, Volume and Issue: 17(843)

Published: July 2, 2024

Mini-G proteins are engineered, thermostable variants of Gα subunits designed to stabilize G protein–coupled receptors (GPCRs) in their active conformations. Because small size and ease use, they popular tools for assessing GPCR behaviors cells, both as reporters receptor coupling subtypes cellular assays quantify compartmentalized signaling at various subcellular locations. Here, we report that overexpression mini-G with cognate GPCRs disrupted endocytic trafficking associated intracellular signaling. In cells expressing the s -coupled glucagon-like peptide 1 (GLP-1R), coexpression , a protein derived from blocked β-arrestin 2 recruitment internalization endosomal GLP-1R These effects did not involve changes phosphorylation or lipid nanodomain segregation. Moreover, found i q also inhibited couple them. Finally, developed an alternative assay using nanobody specific :GPCR complexes (Nb37) affect internalization. Our results have important implications designing methods assess

Language: Английский

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Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers

Science Advances, Journal Year: 2023, Volume and Issue: 9(49)

Published: Dec. 6, 2023

The metabotropic glutamate receptors (mGluRs) are family C, dimeric G protein–coupled (GPCRs), which play critical roles in synaptic transmission. Despite an increasing appreciation of the molecular diversity this family, how distinct mGluR subtypes regulated remains poorly understood. We reveal that different group II/III show markedly beta-arrestin (β-arr) coupling and endocytic trafficking. While mGluR2 is resistant to internalization mGluR3 shows transient β-arr coupling, enables endocytosis recycling, mGluR8 form stable complexes, leads efficient lysosomal targeting degradation. Using chimeras mutagenesis, we pinpoint carboxyl-terminal domain regions control trafficking, including identification splice variant with impaired internalization. then use a battery high-resolution fluorescence assays find heterodimerization further expands regulation. Together, work provides insight into relationship between GPCR/β-arr complex formation trafficking while revealing intricacy regulation mGluRs.

Language: Английский

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The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells

Metabolism, Journal Year: 2021, Volume and Issue: 118, P. 154734 - 154734

Published: Feb. 23, 2021

The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target type 2 diabetes drugs aiming to enhance secretion.Here we show that the protein phosphatase inhibitor 1A (PPP1R1A), expressed in β-cells and its expression reduced dysfunctional lacking MafA upon acute knock down. central regulator GSIS β-cell function. We observed strong correlation MAFA PPP1R1A mRNA levels human islets, moreover, were diabetic islets positively correlated with GLP1-mediated amplification. silencing INS1 (832/13) impaired amplification, PKA-target phosphorylation, mitochondrial coupling efficiency also marker genes MafA, Pdx1, NeuroD1 Pax6. Our results demonstrate transcription factor required function contributed dedifferentiation during diabetes. Loss may explains unresponsiveness patients GLP1R-based treatments.

Language: Английский

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