Subunit-Specific Regulation of N-Methyl-D-aspartate (NMDA) Receptor Trafficking by SAP102 Splice Variants

Synapse-associated protein 102 (SAP102) is a scaffolding protein abundantly expressed early in development that mediates glutamate receptor trafficking during synaptogenesis. Mutations in human SAP102 have been reported to cause intellectual disability, which is consistent with its important role during early postnatal development. SAP102 contains PDZ, SH3 and guanylate kinase (GK)-like domains, which mediate specific proteinprotein interactions. SAP102 binds directly to N-methyl-D-aspartate receptors (NMDARs), anchors receptors at synapses and facilitates transduction of NMDAR signals. Proper localization of SAP102 at the postsynaptic density (PSD) is essential to these functions. However, how SAP102 is targeted to synapses is unclear. In the current study, we find that synaptic localization of SAP102 is regulated by alternative splicing. The SAP102 splice variant that possesses a C-terminal insert (I2) between the SH3 and GK domains is highly enriched at dendritic spines. We also show that there is an intramolecular interaction between the SH3 and GK domains in SAP102 but that the I2 splicing does not influence SH3-GK interaction. Previously, we have shown that SAP102 expression promotes spine lengthening. We now find that the spine lengthening effect is independent of the C-terminal alternative splicing of SAP102. In addition, expression of I2-containing SAP102 isoforms is regulated developmentally. Knockdown of endogenous I2-containing SAP102 isoforms differentially affect NMDAR surface expression in a subunitspecific manner. These data shed new light on the role of SAP102 in the regulation of NMDAR trafficking. PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs), including PSD-95, SAP102, PSD-93 and SAP97, are a family of scaffolding proteins highly enriched in the PSD and play essential roles in synaptic organization and plasticity (1). They interact directly or indirectly with major types of glutamate receptors. http://www.jbc.org/cgi/doi/10.1074/jbc.M114.599969 The latest version is at JBC Papers in Press. Published on January 2, 2015 as Manuscript M114.599969 Copyright 2015 by The American Society for Biochemistry and Molecular Biology, Inc. by gest on N ovem er 9, 2017 hp://w w w .jb.org/ D ow nladed from