Differential Regulation of AMPA Receptor Subunit Trafficking by Palmitoylation of Two Distinct Sites

Calcium-Permeable AMPA Receptor Plasticity Is Mediated by Subunit-Specific Interactions with PICK1 and NSF

Autoinactivation of Neuronal AMPA Receptors via Glutamate-Regulated TARP Interaction

An Essential Role for PICK1 in NMDA Receptor-Dependent Bidirectional Synaptic Plasticity

TARP Subtypes Differentially and Dose-Dependently Control Synaptic AMPA Receptor Gating

AMPA Receptor Subunit-Specific Regulation by a Distinct Family of Type II TARPs

The Expanding Social Network of Ionotropic Glutamate Receptors: TARPs and Other Transmembrane Auxiliary Subunits

Synaptic AMPA Receptor Plasticity and Behavior

Long-Term Depression of Kainate Receptor-Mediated Synaptic Transmission

Block of Kainate Receptor Desensitization Uncovers a Key Trafficking Checkpoint

NGPF2 triggers synaptic scaling up through ALK-LIMK-cofilin-mediated mechanisms.

Light-Induced Plasticity of Synaptic AMPA Receptor Composition in Retinal Ganglion Cells

Molecular Dissociation of the Role of PSD-95 in Regulating Synaptic Strength and LTD

Oxygen and glucose deprivation (OGD) induces delayed cell death in hippocampal CA1 neurons via Ca2+/Zn2+-permeable, GluR2-lacking AMPA receptors (AMPARs). Following OGD, synaptic AMPAR currents in hippocampal neurons show marked inward rectification and increased sensitivity to channel blockers selective for GluR2-lacking AMPARs. This occurs via two mechanisms: a delayed down-regulation of GluR2 mRNA expression and a rapid internalization of GluR2-containing AMPARs during the OGD insult, which are replaced by GluR2-lacking receptors. The mechanisms that underlie this rapid change in subunit composition are unknown. Here, we demonstrate that this trafficking event shares features in common with events that mediate long term depression and long term potentiation and is initiated by the activation of N-methyl-d-aspartic acid receptors. Using biochemical and electrophysiological approaches, we show that peptides that interfere with PICK1 PDZ domain interactions block the OGD-induced switch in subunit composition, implicating PICK1 in restricting GluR2 from synapses during OGD. Furthermore, we show that GluR2-lacking AMPARs that arise at synapses during OGD as a result of PICK1 PDZ interactions are involved in OGD-induced delayed cell death. This work demonstrates that PICK1 plays a crucial role in the response to OGD that results in altered synaptic transmission and neuronal death and has implications for our understanding of the molecular mechanisms that underlie cell death during stroke.

Coassembly of Two GluR6 Kainate Receptor Splice Variants within a Functional Protein Complex

Calcium/calmodulin-dependent protein kinase II (CaMKII), a major component of the postsynaptic density (PSD) of excitatory synapses, plays a key role in the regulation of synaptic function in the mammalian brain. Although many postsynaptic substrates for CaMKII have been characterized in vitro, relatively little is known about their phosphorylation in vivo. By tagging synaptic proteins with a peptide substrate specific for CaMKII and expressing them in cultured neurons, we have visualized substrate phosphorylation by CaMKII at intact synapses. All substrates tested were strongly phosphorylated by CaMKII in HEK293 cells. However, activity-dependent phosphorylation of substrates at synapses was highly selective in that the glutamate receptor subunits NR2B and GluR1 were poorly phosphorylated whereas PSD-95 and Stargazin, proteins implicated in the scaffolding and trafficking of AMPA receptors, were robustly phosphorylated. Phosphatase activity limited phosphorylation of Stargazin but not NR2B and GluR1. These results suggest that the unique molecular architecture of the PSD results in highly selective substrate discrimination by CaMKII.