Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation.

Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration.

CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors.

SAP97 interacts with AMPA receptors (AMPARs) and NMDA receptors (NMDARs) during sorting and trafficking to synapses. Here we addressed how SAP97 distinguishes between AMPARs and NMDARs and what role the adaptor/scaffold protein, CASK, plays in the process. Using intramolecular SAP97 Förster resonance energy transfer sensors, we demonstrated that SAP97 is in "extended" or "compact" conformations in vivo.

SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway.

Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts.