An examination of the divergent spatiotemporal signaling of GLP-1R versus GIPR in pancreatic beta cells DOI Creative Commons
Yusman Manchanda, Stavroula Bitsi,

Shiqian Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 17, 2022

Abstract The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR), are class B GPCRs 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 favoured versus GIPR as a target due responses blunted T2D patients conflicting effects agonists antagonists improving glucose tolerance preventing weight gain. There is, however, recently renewed interest biology following realisation that can be restored after an initial period blood normalization recent development dual GLP-1R-GIPR with superior capacity control levels weight. importance trafficking subcellular signaling outputs is well established, but little known about pattern spatiotemporal from cells. Here we have directly compared characteristics both receptors cells, finding striking differences their propensities internalization, recycling, degradation, plasma membrane endosomal activity, potential implications receptor-specific cell function.

Language: Английский

Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells DOI Creative Commons
Yusman Manchanda, Stavroula Bitsi,

Shiqian Chen

et al.

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

Citations

29
Biased agonism and polymorphic variation at the GLP-1 receptor: Implications for the development of personalised therapeutics DOI Creative Commons
Liliane El Eid, Christopher A. Reynolds, Alejandra Tomás

et al.

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

Citations

29
Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling DOI
Yusman Manchanda, Liliane El Eid, Affiong I Oqua

et al.

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

Citations

7
Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists DOI Creative Commons
Charlotte E. Hinds,

Ellie Peace,

Shiqian Chen

et al.

Diabetes Obesity and Metabolism, Journal Year: 2023, Volume and Issue: 26(1), P. 65 - 77

Published: Oct. 5, 2023

Abstract Aim Earlier studies have shown that peptide glucagon‐like peptide‐1 receptor (GLP‐1R) agonists with reduced β‐arrestin recruitment show enhanced anti‐hyperglycaemic efficacy through avoidance of GLP‐1R desensitization. However, the ligand modifications needed to decrease usually also reduces affinity, therefore higher doses are needed. Here we aimed develop new, long‐acting, G protein‐biased acute signalling potency comparable semaglutide, provide insights into specific experimental and therapeutic scenarios. Materials Methods New agonist peptides were assessed using a variety in vitro vivo assays. Results First, very substantial reductions required realize fully benefits agonism on blood glucose lowering mice, more moderate being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects weight loss, which may be jointly attributable its biased action protracted pharmacokinetics. Thirdly, agonist‐specific internalization profiles occur at clinically relevant pharmacological concentrations. Finally, SRB107 cAMP is differentially modulated by single double GLP1R coding variants seen human populations, implications pharmacogenomics. Conclusions Completely abolishing improves mice.

Language: Английский

Citations

11
Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics DOI Creative Commons
Zoe Tasma, Michael L. Garelja, Aqfan Jamaluddin

et al.

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108846 - 108846

Published: April 1, 2025

Class B G protein-coupled receptors (GPCRs) are a subfamily of 15 peptide hormone with diverse roles in physiological functions and disease pathogenesis. Over the past decade, several novel therapeutics targeting these have been approved for conditions like migraine, diabetes, obesity, many which ground-breaking first-in-class. Most agonist analogues modified endogenous sequences to enhance receptor activation or stability. Several small molecule monoclonal antibody antagonists also late-stage development. Differences sequence structure therapeutic ligands lead distinct signalling profiles, including biased behaviour inhibition specific pathways. Understanding this pharmacology offers unique development opportunities improving efficacy reducing adverse effects. This review summarises current knowledge on ligand bias class GPCR drugs, highlights strategies refine exploit their pharmacological discusses key considerations related structure, localisation, regulation developing new therapies.

Language: Английский

Citations

0
Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in β-arrestin 1/2 signaling DOI
Saifei Lei, Qian Meng,

Yan‐Yun Liu

et al.

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 968, P. 176419 - 176419

Published: Feb. 13, 2024

Language: Английский

Citations

2
In vivo and in vitro characterization of GL0034, a novel long‐acting glucagon‐like peptide‐1 receptor agonist DOI
Ben Jones,

Vinod Burade,

Elina Akalestou

et al.

Diabetes Obesity and Metabolism, Journal Year: 2022, Volume and Issue: 24(11), P. 2090 - 2101

Published: June 9, 2022

Abstract Aims To describe the in vitro characteristics and antidiabetic vivo efficacy of novel glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) GL0034. Materials Methods Glucagon‐like (GLP‐1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis recycling were measured using HEK293 INS‐1832/3 cells expressing human GLP‐1R. Insulin secretion was cells, mouse islets islets. Chronic administration studies to evaluate weight loss glycaemic effects performed db/db diet‐induced obese mice. Results Compared leading GLP‐1RA semaglutide, GL0034 showed increased affinity potency‐driven bias favour cAMP over GLP‐1R β‐arrestin‐2 recruitment. secretory responses similar for both ligands. (6 nmol/kg) led at least as much lowering blood glucose did semaglutide a higher dose (14 nmol/kg). Conclusions is G protein‐biased that shows powerful mice, may serve promising new patients with type 2 diabetes.

Language: Английский

Citations

7
Cardiovascular effects of GLP-1 receptor agonism DOI

Raymond J. Winquist,

Valentin K. Gribkoff

Advances in pharmacology, Journal Year: 2022, Volume and Issue: unknown, P. 213 - 254

Published: Jan. 1, 2022

Language: Английский

Citations

6
Expression of mini-G proteins specifically halt cognate GPCR trafficking and intracellular signalling DOI Creative Commons
Yusman Manchanda, Zenouska Ramchunder, Maria M. Shchepinova

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Nov. 25, 2021

Abstract Mini-G proteins are engineered thermostable variants of Gα subunits designed to specifically stabilise G protein-coupled receptors (GPCRs) in their active conformation for structural analyses. Due smaller size and ease use, they have become popular tools recent years assess specific GPCR behaviours cells, both as reporters receptor coupling each protein subtype in-cell assays quantify compartmentalised signalling from a range subcellular locations. Here, we describe previously unappreciated consequence the co-expression mini-G with cognate GPCRs, namely profound disruption trafficking intracellular caused by coupled affected receptor. We studied Gαs-coupled pancreatic beta cell class B glucagon-like peptide-1 (GLP-1R) model detail molecular consequences derived this effect, including complete halt β-arrestin-2 recruitment internalisation, despite near-normal levels GRK2 lipid nanodomain segregation, well endosomal GLP-1R s co-expression. also extend our analysis other prototypical GPCRs covering spectrum preferences, unveil widely conserved phenomenon internalisation blockage particular Our results important implications design methods signalling. present an alternative adapted bystander assay which substitute nanobody, Nb37, specificity Gαs:GPCR complexes no deleterious effect on capacity internalisation.

Language: Английский

Citations

5
An examination of the divergent spatiotemporal signaling of GLP-1R versus GIPR in pancreatic beta cells DOI Creative Commons
Yusman Manchanda, Stavroula Bitsi,

Shiqian Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 17, 2022

Abstract The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR), are class B GPCRs 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 favoured versus GIPR as a target due responses blunted T2D patients conflicting effects agonists antagonists improving glucose tolerance preventing weight gain. There is, however, recently renewed interest biology following realisation that can be restored after an initial period blood normalization recent development dual GLP-1R-GIPR with superior capacity control levels weight. importance trafficking subcellular signaling outputs is well established, but little known about pattern spatiotemporal from cells. Here we have directly compared characteristics both receptors cells, finding striking differences their propensities internalization, recycling, degradation, plasma membrane endosomal activity, potential implications receptor-specific cell function.

Language: Английский

Citations

1