Gephyrin

Abstract: The tubulin-binding protein gephyrin, which anchors the inhibitory glycine receptor (GlyR) at postsynaptic sites, decorates GABAergic postsynaptic membranes in various brain regions, and postsynaptic gephyrin clusters are absent from cortical cultures of mice deficient for the GABAA receptor γ2 subunit. Here, we investigated the postsynaptic clustering of GABAA receptors in gephyrin knock-out (geph −/−) mice. Both in brain sections and cultured hippocampal neurons derived fromgeph −/− mice, synaptic GABAA receptor clusters containing either the γ2 or the α2 subunit were absent, whereas glutamate receptor subunits were normally localized at postsynaptic sites. Western blot analysis and electrophysiological recording revealed that normal levels of functional GABAAreceptors are expressed in geph −/− neurons, however the pool size of intracellular GABAA receptors appeared increased in the mutant cells. Thus, gephyrin is required for the synaptic localization of GlyRs and GABAA receptors containing the γ2 and/or α2 subunits but not for the targeting of these receptors to the neuronal plasma membrane. In addition, gephyrin may be important for efficient membrane insertion and/or metabolic stabilization of inhibitory receptors at developing postsynaptic sites.

Abstract: The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated 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.