14-3-3ζ Mediates GABAAR Activation by Interacting with BIG1
Cuixian Li1, Shen Huang1, Jin Peng2
1Experiment Teaching & Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Molecular Neurobiology
|December 23, 2022
Summary
The protein 14-3-3ζ interacts with BIG1 to regulate GABAA receptor (GABAAR) surface expression, crucial for brain inhibition and potentially treating neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Fast synaptic inhibition in the mammalian brain relies on GABAA receptors (GABAARs).
- Proper cell surface expression of GABAARs is vital for neurodevelopment and GABAergic transmission.
- BIG1, a GABAAR binding partner, is known to mediate GABAAR trafficking to the cell surface, but its regulation is unclear.
Purpose of the Study:
- To identify regulatory mechanisms of BIG1-mediated GABAAR trafficking.
- To investigate the role of the newly identified protein 14-3-3ζ in GABAAR surface expression.
Main Methods:
- In vitro and in vivo protein interaction studies (co-immunoprecipitation).
- Confocal microscopy to assess protein localization in hippocampal neurons.
- RNA interference (siRNA) to deplete 14-3-3ζ and BIG1.
- GABAAR agonist treatment to observe expression changes.
Main Results:
- 14-3-3ζ interacts with GABAAR β subunit and BIG1, localizing to neuronal soma, dendrites, and axons.
- Overexpression of 14-3-3ζ enhances BIG1 surface expression and its binding to GABAAR.
- Depletion of 14-3-3ζ reduces BIG1-GABAAR interaction, decreasing surface levels of both proteins and chloride ion influx.
Conclusions:
- The 14-3-3ζ and BIG1 complex is essential for regulating GABAAR membrane expression.
- This pathway is critical for GABAergic synaptic transmission.
- The 14-3-3ζ/BIG1 interaction presents a potential therapeutic target for neurological disorders affecting GABAergic signaling.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
7.4K
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...
7.4K
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.4K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.4K
01:21G-Protein Gated Ion Channels
4.7K
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...
Sensory...
4.7K
01:11IP3/DAG Signaling Pathway
12.3K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.3K
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
517
γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...
517
02:14GTPases and their Regulation
8.5K
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
Large G-proteins,...
8.5K