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Related Concept Videos

GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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G Protein-coupled Receptors01:15

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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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Activation and Inactivation of G Proteins01:22

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Glucagon-like Receptor Agonists01:24

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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Glucagon-like Peptide-1 Receptor (GLP-1R) Signaling: Making the Case for a Functionally Gs Protein-Selective GPCR.

Anastasios Lymperopoulos1, Victoria L Altsman1, Renee A Stoicovy1

  • 1Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.

International Journal of Molecular Sciences
|August 14, 2025
PubMed
Summary

Glucagon-like peptide-1 receptor (GLP-1R) agonists show therapeutic success. Evidence suggests GLP-1R functions as a Gs-selective receptor, unlike GIPR, impacting drug development for obesity and diabetes.

Keywords:
G protein signalingagonist potencybiased signalingcyclic adenosine monophosphatedesensitizationglucagon family receptor poly-agonistglucagon-like peptide-1 receptorglucose-dependent insulinotropic peptide receptorβarrestin signaling

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Area of Science:

  • Pharmacology
  • Endocrinology
  • Molecular Biology

Background:

  • Glucagon-like peptide-1 receptor (GLP-1R) agonists are successful treatments for diabetes and obesity.
  • Glucagon family receptors (GCGR, GLP-1R, GIPR) are Class B1 G protein-coupled receptors (GPCRs) involved in insulin secretion.
  • GPCRs typically desensitize via βarrestin interactions, but GLP-1R may resist this.

Purpose of the Study:

  • To investigate the signaling and desensitization mechanisms of GLP-1R compared to GIPR.
  • To present evidence for GLP-1R as a Gs-selective receptor.
  • To discuss implications for developing poly-ligands targeting GLP-1R.

Main Methods:

  • Review of experimental evidence on GLP-1R and GIPR signaling pathways.
  • Analysis of GPCR desensitization mechanisms involving G proteins and βarrestins.
  • Discussion of receptor trafficking and lipid raft interactions.

Main Results:

  • GLP-1R signaling is characterized by robust and prolonged cAMP production, suggesting lack of desensitization.
  • GIPR signaling heavily involves βarrestins, leading to significant desensitization, internalization, and downregulation.
  • GLP-1R exhibits properties consistent with a Gs-selective receptor, distinct from GIPR.

Conclusions:

  • GLP-1R appears to be a phenotypically Gs-selective receptor, resisting desensitization.
  • The distinct signaling and desensitization profiles of GLP-1R and GIPR have significant implications for therapeutic strategies.
  • Understanding these differences is crucial for the rational design of novel GLP-1R-based poly-ligands for metabolic diseases.