Related Experiment Video
Updated: Jul 25, 2025
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
8.9K
Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits
Jong-Chan Park1, Alex Luebbers1, Maria Dao2
1Department of Biochemistry & Cell Biology, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA.
Molecular Cell
|June 30, 2023
Summary
The neuronal protein GINIP regulates inhibitory G protein-coupled receptor (GPCR) signaling by favoring Gβγ over Gα subunits. This mechanism prevents neurotransmission imbalances and reduces seizure susceptibility in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- G-protein-coupled receptors (GPCRs) are crucial for neuromodulation.
- GPCR activation involves heterotrimeric G proteins (Gαβγ), traditionally viewed as independent signaling units.
- Mechanisms ensuring coordinated Gα and Gβγ signaling remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanism of G protein signaling bias.
- To investigate the role of neuronal protein GINIP in GPCR response fidelity.
- To determine the impact of this regulation on neurotransmission and seizure susceptibility.
Main Methods:
- Investigated G protein activation and effector interactions.
- Utilized biochemical assays to study GINIP binding to Gαi-GTP.
- Examined the effect of GINIP on adenylyl cyclase activity and RGS protein interaction.
- Assessed seizure susceptibility in a mouse model.
Main Results:
- Discovered that GINIP binds tightly to Gαi-GTP, inhibiting its effector association and RGS protein interaction.
- Demonstrated that GINIP dampens Gαi-GTP signaling while enhancing Gβγ signaling.
- Showed this GINIP-mediated bias is essential for preventing neurotransmission imbalances.
- Linked this mechanism to reduced seizure susceptibility in mice.
Conclusions:
- GINIP introduces a novel regulatory paradigm, biasing inhibitory GPCR signaling towards Gβγ.
- This regulation fine-tunes neurotransmission by modulating Gα and Gβγ signaling outputs.
- The findings reveal a critical mechanism for maintaining neuronal homeostasis and preventing hyperexcitability disorders.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
7.3K
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...
7.3K
01:30Transducer Mechanism: G Protein–Coupled Receptors
2.1K
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,...
GPCRs are also called heptahelical,...
2.1K
01:12GPCR Desensitization
6.2K
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...
6.2K
01:09GPCRs Regulate Adenylyl Cylase Activity
5.7K
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...
5.7K
01:21G-protein Coupled Receptors
120.3K
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.
120.3K
01:15G Protein-coupled Receptors
12.3K
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...
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...
12.3K