Synapse-associated protein 97 selectively associates with a subset of AMPAreceptors early in their biosynthetic pathway

The regulation of AMPA receptors at the postsynaptic membrane is a fundamen tal component of synaptic plasticity. In the hippocampus, the induction of long-term potentiation increases the delivery of GluR1, a major AMPA recept or subunit in hippocampal pyramidal neurons, to the synaptic plasma membran e through a mechanism that requires the PDZ binding domain of GluR1. Synaps e-associated protein 97 (SAP97), a member of the membrane-associated guanyl ate kinase family, is believed to associate with AMPA receptors (AMPARs) co ntaining the GluR1 subunit, but the functional significance of these intera ctions is unclear. We investigated the interaction of GluR1 with SAP97, the only PDZ protein known to interact with GluR1. We find that interactions i nvolving SAP97 and GluR1 occur early in the secretory pathway, while the re ceptors are in the endoplasmic reticulum or cis-Golgi. In contrast, few syn aptic receptors associate with SAP97, suggesting that SAP97 dissociates fro m the receptor complex at the plasma membrane. We also show that internaliz ation of GUM, as triggered by NMDAR activation, does not require SAP97. The se results implicate GluR1-SAP97 interactions in mechanisms underlying AMPA receptor targeting.