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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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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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GPCR Desensitization01:12

GPCR Desensitization

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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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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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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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G-protein Coupled Receptors01:21

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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Related Experiment Video

Updated: Jun 13, 2025

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Positive allosteric modulation of a GPCR ternary complex.

Wessel A C Burger1,2, Christopher J Draper-Joyce1, Celine Valant1

  • 1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

Science Advances
|September 11, 2024
PubMed
Summary
This summary is machine-generated.

Positive allosteric modulators stabilize the G protein-coupled receptor (GPCR) ternary complex, enhancing signaling rates. This finding advances understanding of allosteric modulator function and aids therapeutic design.

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Area of Science:

  • Biochemistry
  • Molecular Pharmacology
  • Structural Biology

Background:

  • G protein-coupled receptors (GPCRs) form high-affinity ternary complexes with agonists and G proteins upon activation.
  • Allosteric modulators bind distinct sites, influencing orthosteric ligand affinity and efficacy.
  • Characterizing allosteric modulator effects on the active GPCR-G protein complex is challenging in traditional assays.

Purpose of the Study:

  • To investigate the influence of positive allosteric modulators on the high-affinity GPCR-G protein ternary complex.
  • To elucidate the mechanism by which allosteric modulators affect orthosteric ligand signaling.
  • To provide insights for the development of allosteric therapeutics.

Main Methods:

  • Purification of the M2 muscarinic acetylcholine receptor.
  • Reconstitution of the purified receptor into nanodiscs.
  • Biochemical assays to characterize ternary complex formation and signaling.

Main Results:

  • Positive allosteric modulators stabilize the agonist-bound, high-affinity GPCR-G protein ternary complex.
  • Stabilization of the ternary complex, in the presence of nucleotides, enhances the initial signaling rate.
  • Demonstrated a method to study these interactions in a purified system.

Conclusions:

  • Allosteric modulators play a crucial role in stabilizing the active GPCR-G protein complex.
  • Understanding this stabilization is key to comprehending allosteric ligand-receptor-G protein interactions.
  • Findings facilitate the rational design of novel allosteric drugs targeting GPCRs.