Rapsyn, gephyrin, and PSD-95 as scaffolding proteins and signaling molecules. An illustration of rapsyn, gephyrin, and PSD-95 (red) and some of the scaffolding proteins (blue) and signaling molecules (yellow) with which they associate. A) At acetylcholine receptor clusters, rapsyn binds the intracellular portion of the receptor subunits. The activation of rapsyn and the clustering of receptors are initiated by agrin or laminin, and rapsyn stabilizes receptors through a direct association with β-dystroglycan and β-catenin. Cytoskeletal reorganization is controlled by the association of rapsyn to calpain. B) At inhibitory synapses, glycine and/or GABA receptors mediate neurotransmission. The activation of gephyrin clustering requires glycine receptor activity, and gephyrin binds directly to the intracellular loop of the glycine receptor γ-subunit. Direct binding of gephyrin to the GABA receptor has not been observed, but gephyrin is required for γ₂-GABA receptor subunit clustering. Like rapsyn, gephyrin links receptors to the intracellular cytoskeleton (through mena/VASP) and regulates signaling through interactions with collybistin. C) The clustering of AMPA, NMDA, and nACh receptors at excitatory central synapses is mediated by PDZ proteins, including the most prevalent member of that family, PSD-95. PSD-95 binds directly to the NMDA receptor and indirectly to AMPA receptors through intermediate TARP and/or SAP-97 proteins. Although PSD-95 associates with nAChRs in central synapses, it is not known whether this interaction is direct.

Receptor and receptor-associated protein dynamics at peripheral cholinergic and central glutamatergic synapses. A) Model suggesting the way by which AChR-associated rapsyn scaffolding protein (red arrows) is removed from and inserted into the neuromuscular junction. There are two possibilities by which rapsyn can be removed: 1) rapsyn migrates with receptors into the perijunctional region (as a transitory station) and then dissociates from receptor before being internalized or translocated along the membrane, 2) rapsyn is directly internalized from the junctional region. The fact that receptors and rapsyn are differentially regulated implies that rapsyn does not follow the same path as the receptor. To maintain normal equilibrium, the insertion rate of rapsyn must equal the removal rate. The insertion could occur either into the perijunctional pool, the junctional pool, or both as denoted by question marks. The recycling of rapsyn is also not yet resolved. B) Model suggesting the way PSD-95 is removed from and inserted into the excitatory synapse. As with rapsyn in peripheral cholinergic synapses, AMPA receptor dynamics have been relatively well characterized (black arrows) while the details of PSD-95 insertion, removal and recycling at central synapses are largely unknown (red arrows).