Trends in Neurosciences
ReviewClustering of inhibitory neurotransmitter receptors at developing postsynaptic sites: the membrane activation model
Section snippets
Gephyrin is essential for the formation of postsynaptic GlyR and GABAA-receptor clusters
Gephyrin22 was originally identified as a peripheral membrane protein23 that co-purified with the mammalian GlyR (24, 25). Biochemical and electron microscopy studies have shown that gephyrin is a major structural component of inhibitory postsynaptic membranes that anchors GlyRs to the subsynaptic cytoskeleton8. First, gephyrin decorates the cytoplasmic face of postsynaptic membrane specializations in spinal cord and other regions of the CNS and co-extends with the GlyR immunoreactive receptor
Gephyrin, a synaptic scaffolding protein?
Gephyrin is encoded by a large and highly mosaic gene that is expressed in all mammalian tissues examined22. Its coding region encompasses at least 29 exons, seven of which are subject to alternative splicing to generate a diverse set of gephyrin isoforms48. The N- and C-terminal regions of gephyrin display high homology to proteins involved in molybdenum cofactor (MoCo) biosynthesis, and gephyrin has been shown to be essential for the synthesis of this coenzyme in peripheral organs (Box 1).
Lipid-anchored gephyrin interaction partners
Recent biochemical and yeast two-hybrid experiments have identified a number of gephyrin binding partners (Table 1). These include the lipid-binding proteins collybistin and profilin and the kinase RAFT1 (rapamycin and FKBP12 target); the latter might be implicated in the regulation of subsynaptic protein synthesis (Box 2).
The gephyrin-binding protein collybistin11 belongs to the family of diffuse B-cell lymphoma-like (dbl-like) GDP/GTP-exchange factors (GEFs), which activate small G proteins
Signaling mechanisms involved in inhibitory receptor clustering
One of the central questions of synapse formation is how the pre- and postsynaptic compartments become aligned. Studies at the neuromuscular junction have shown that electrical activity has an important role in restricting ACh-receptor synthesis to synaptic sites55. In embryonic spinal neurons, inhibition of GlyR activation by the specific antagonist strychnine prevents postsynaptic GlyR clustering and induces the internalization of GlyRs into putative endosomal structures46, 56. Similarly,
Concluding remarks
The recent identification of lipid-anchored binding partners of gephyrin has opened novel concepts on how Ca2+ and PI3K-driven activation of trinucleotide-dependent signaling cascades might contribute to the postsynaptic localization and translational control of inhibitory neurotransmitter receptors. The effector proteins involved are likely to also control the dynamic changes of the actin, and possibly tubulin, cytoskeleton that accompany synaptogenesis, and to trigger MAPK and other kinases
Note added in proof
The authors wish to acknowledge recent data70, which shows that in highly mature hippocampal cultures postsynaptic gephyrin clusters are not disrupted by microtubule and actin filament depolymerizing agents. Thus, the gephyrin scaffold that forms at developing synaptic sites might become stabilized at later developmental stages.
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A proline-rich motif in the large intracellular loop of the glycine receptor α1 subunit interacts with the Pleckstrin homology domain of collybistin
2021, Journal of Advanced ResearchCitation Excerpt :Mutagenesis in the PPII motif neither alters GlyR surface targeting nor receptor function, but appears to affect synaptic anchoring of GlyRα1 subunits. The large intracellular loop of the inhibitory GlyR contains numerous motifs for intracellular interaction [2,4,17,18,42–45] and modulation of receptor function [7,17,34,46,47]. Here, we investigated the function of a proline-rich motif, 365PPPAPSKSP373, which forms a PPII helix that is located in the intracellular TM3-4 loop of the human GlyRα1 subunit.
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