Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2

Abstract

Significance Clathrin-mediated endocytosis (CME) of glutamate receptors from the postsynaptic membrane is central for adjusting synaptic strength and is thought to be the substrate for various forms of synaptic plasticity. The role of the actin cytoskeleton in CME is recognized as fundamental but remains poorly understood, and we lack a mechanistic understanding of the cytoskeletal/CME association, its functional consequences, and its regulation. Here we identify the activity-regulated synaptic nuclear envelope 1 gene product candidate plasticity gene 2 (CPG2) as a direct functional link between the cytoskeleton and postsynaptic endocytosis, and as a nexus for the interaction of signaling pathways with the endocytic process. CPG2 reversibly associates with F-actin, and this association is positively regulated by PKA and is an important regulator of both glutamate receptor internalization and postsynaptic strength.