Gephyrin: a master regulator of neuronal function?

Abstract

The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligandgated chloride channels-namely, type A GABA (GABA(A)) 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. Shiva Tyagarajan graduated as a molecular virologist at the Pennsylvania State University (USA) and later trained as a neurobiologist during his post-doctoral studies at the University of Zurich. He is currently a group leader and the research focus of his group is to elucidate molecular and cellular mechanisms that couple transcriptional and post-transcriptional programs to regulate GABAergic synaptic plasticity. 3 AbstractThe neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated Cl  channels, namely the GABA A 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 gephyrin postsynaptic clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, posttranslational 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.On-line summary  Gephyrin is a multi-functional protein, responsible for Moco biosynthesis in all organisms, and for postsynaptic clustering of glycine receptors and GABAA receptors in vertebrate CNS  Gephyrin forms a protein scaffold by self-assembly from trimeric complexes, which interacts with numerous, structurally different proteins, in order to form a high ordered signalling complex in glycinergic and GABAergic synapses  Gephyrin function as a scaffolding protein is regulated by alternate mRNA splicing and by multiple post-transcriptional and posttranslational modifications, which only begin to be understood.  Regulation of gephyrin scaffold by multiple signallin...

Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation

“…Also gephyrin can interact with various partners, including neuroligin 2, collibystin, or even Cdc42 to regulate cluster formation and GABA A R aggregation (7,9). These results are thus consistent with the idea that gephyrin acts as a molecular hub regulating the formation and extension of the inhibitory postsynaptic density (12). Our data now indicate that gephyrin phosphorylation on Ser305 plays a critical role in the activitydependent regulation of these clustering mechanisms.…”

“…The distribution and clustering of GABA A Rs at synapses is tightly regulated through interactions with the scaffolding protein gephyrin, one of the main structural constituent of inhibitory postsynaptic densities. Gephyrin forms multimeric complexes that allow the anchoring of GABA A Rs (6) via molecular mechanisms that include phosphorylation and interactions with the guanine-nucleotide exchange factor collybistin (7)(8)(9)(10)(11)(12). In addition to changes in inhibitory strength, more recent in vivo experiments revealed that inhibitory synapses are also dynamic structures that can be formed and eliminated in response to sensory experience (13)(14)(15).…”

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

“…We then examined which types of molecules construct postsynaptic membrane specializations at dopamine synapses. From their symmetric nature, we examined expression levels of the following GABAergic postsynaptic proteins: GABA A Rα1, gephyrin (a scaffolding protein interacting with GABA A and glycine receptors) and NL2 (a synaptic adhesion protein interacting with GABA A receptors and gephyrin) (20,21). All three proteins were clustered in the neuropil, and tightly apposed to VIAAT-labeled GABAergic (Fig.…”

Gephyrin: a central GABAergic synapse organizer

“…Gephyrin is the most extensively studied scaffold responsible for organizing the inhibitory postsynaptic density, which is essential for clustering of glycine and γ-aminobutyric acid type A (GABA A ) receptors, inhibitory synaptic transmission and long-term potentiation (reviewed in refs [4][5][6]. Since the discovery of gephyrin in 1982 by Heinrich Betz's group, 7 its biochemical and cellular properties have been extensively studied.…”