Gephyrin is a multifunctional protein that is responsible for molybdenum cofactor biosynthesis in all organisms and for postsynaptic clustering of glycine receptors and type A GABA receptors in the vertebrate CNS.
Gephyrin self-assembles to form a protein scaffold, which interacts with numerous, structurally different proteins to form a highly ordered signalling complex in glycinergic and GABAergic synapses.
Gephyrin's function as a scaffolding protein is regulated by alternative mRNA splicing and by multiple post-transcriptional and post-translational modifications, which are only beginning to be understood.
Regulation of the gephyrin scaffold by multiple signalling cascades modulates the formation and plasticity of GABAergic synapses and thereby the strength of GABAergic transmission.
Because signals impinging on gephyrin post-translational modification are activated by excitatory neurotransmission and increased intracellular calcium concentration, the gephyrin scaffold may form an intracellular hub that modulates synaptic homeostasis and excitatory–inhibitory balance.
Abnormal GABAergic transmission during brain development, possibly brought about or at least linked to impaired gephyrin regulation, might have enduring structural and functional consequences in the adult brain and might contribute to the pathophysiology of major neurological and neuropsychiatric diseases.
The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated chloride channels — namely, type A GABA (GABAA) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein–protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.
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This study was supported by the Swiss National Science Foundation. We are grateful to P. Panzanelli (University of Turin, Italy) for the fruitful collaboration and for providing figure 1D.
The authors declare no competing financial interests.
- Postsynaptic density
(PSD). A generic term derived from the ultrastructural appearance of the postsynaptic membrane, which is thicker and more electron-dense than the plasma membrane. This owes to an accumulation of molecules (for example, trans-synaptic extracellular matrix proteins, neurotransmitter receptors and effector proteins) at such regions, which are held together by scaffolding proteins that are bound to the actin cytoskeleton.
- Inhibitory neurotransmission
Inhibitory neurotransmission may be mediated by several neurotransmitters, particularly GABA and glycine, which lower the resting membrane potential and increase membrane conductance of neurons by activating ionotropic receptors and, in the case of GABA, reduce excitability of neurons by promoting G protein-mediated activation of voltage-gated potassium and inhibition of calcium channels.
- Post-translational modifications
Structural changes (for example, the formation of disulphide bonds between two amino acids) or reversible attachment of functional residues (for example, a phosphate or acetate group), a small protein (for example, ubiquitin or small ubiquitin-related modifier (SUMO)) or a lipid (for example, palmitic acid) to specific residues in a protein, which are mediated by a dedicated enzyme or enzymatic pathway and confer novel properties to the modified protein (for example, functional activation, membrane anchorage or differential targeting).
- Cys-loop ligand-gated ion channels
A subfamily of neurotransmitter receptors, comprising the prototypic nicotinic acetylcholine receptor, type A GABA (GABAA) receptors, glycine receptors, and 5-hydroxytryptamine type 3 receptors; these receptors are integral ion channels that mediate fast synaptic transmission and have a pentameric homo- or heteromeric subunit structure.
A protein that comprises two non-covalently bound protein products, α-dystroglycan (an extracellular matrix protein) and β-dystroglycan (a transmembrane protein), which are encoded from two exons of DAG1; the proteins products are key constituents of the dystrophin–glycoprotein complex (DGC).
- Protein scaffold
A high-order molecular arrangement of proteins, forming a highly structured, crystal-like lattice by self-assembly or through specific protein interaction motives and serving to anchor other proteins (notably neurotransmitter receptors and effector molecules) at specific subcellular sites.
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Tyagarajan, S., Fritschy, JM. Gephyrin: a master regulator of neuronal function?. Nat Rev Neurosci 15, 141–156 (2014). https://doi.org/10.1038/nrn3670
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