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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 Receptors01:15

G Protein-coupled Receptors

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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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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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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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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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.
GPCRs are also called heptahelical,...
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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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G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

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GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory...
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Related Experiment Video

Updated: Jan 7, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Pathogenic Gαo Mutants Drive Dominant GPCR Coupling in GNAO1 Encephalopathies.

Yonika A Larasati1, Camille Rabesahala de Meritens1, Miriam Stoeber2

  • 1Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 29, 2025
PubMed
Summary

Mutations in GNAO1 cause neurodevelopmental disorders by disrupting Gαo protein interactions with G protein-coupled receptors (GPCRs). Severe variants impair receptor function, highlighting a key disease mechanism.

Keywords:
G protein‐coupled receptors (GPCRs)GNAO1Gαobimolecular fluorescence complementation (BiFC)dystoniaepilepsyheterotrimeric G proteinsmovement disordersneurodevelopmental disorders

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HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice
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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Heterozygous GNAO1 mutations lead to neurodevelopmental disorders, including epileptic encephalopathy and dystonia.
  • The precise molecular mechanisms driving disease dominance in GNAO1 mutations are not fully understood.
  • Previous studies suggested conflicting mechanisms for Gαo mutant dysfunction, involving GPCR engagement or Gβγ sequestration.

Purpose of the Study:

  • To directly visualize and characterize the interaction between mutant Gαo proteins and G protein-coupled receptors (GPCRs).
  • To resolve the apparent contradiction in previously reported Gαo mutant functional mechanisms.
  • To establish a robust assay for studying G protein behavior in genetic diseases.

Main Methods:

  • Development and application of a split-YFP-based bimolecular fluorescence complementation (BiFC) assay.
  • Direct visualization of Gαo protein-GPCR complexes at the plasma membrane.
  • Analysis of receptor phosphorylation and endocytosis in response to Gαo variants.

Main Results:

  • Severe Gαo variants were found to persistently bind activated Gi/o-coupled GPCRs, inhibiting receptor phosphorylation and endocytosis.
  • Milder, dystonia-associated Gαo mutants exhibited near-normal receptor internalization and minimal phosphorylation defects.
  • The split-YFP BiFC assay successfully visualized distinct Gαo-GPCR interaction dynamics.

Conclusions:

  • Persistent dominant GPCR coupling is a hallmark of severe GNAO1-related encephalopathies.
  • The split-YFP BiFC assay provides a powerful tool for investigating mutant G protein function in genetic disorders.
  • Understanding these molecular interactions is crucial for developing targeted therapies for GNAO1-associated diseases.