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

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

A key neuronal mechanism for adjusting excitatory synaptic strength is clathrin-mediated endocytosis of postsynaptic glutamate receptors (GluRs). The actin cytoskeleton is critical for clathrin-mediated endocytosis, yet we lack a mechanistic understanding of its interaction with the endocytic process and how it may be regulated. Here we show that F-actin in dendritic spines physically binds the synaptic nuclear envelope 1 gene product candidate plasticity gene 2 (CPG2) in a PKA-dependent manner, and that this association is required for synaptic GluR internalization. Mutating two PKA sites on CPG2 disrupts its cytoskeletal association, attenuating GluR endocytosis and affecting the efficacy of synaptic transmission in vivo. These results identify CPG2 as an F-actin binding partner that functionally mediates interaction of the spine cytoskeleton with postsynaptic endocytosis. Further, the regulation of CPG2/F-actin association by PKA provides a gateway for cellular control of synaptic receptor internalization through second messenger signaling pathways. Recent identification of human synaptic nuclear envelope 1 as a risk locus for bipolar disorder suggests that CPG2 could play a role in synaptic dysfunction underlying neuropsychiatric disease.

Year of Publication
2013
Journal
Proc Natl Acad Sci U S A
Volume
110
Issue
47
Pages
E4548-56
Date Published
2013 Nov 19
ISSN
1091-6490
DOI
10.1073/pnas.1318860110
PubMed ID
24191017
PubMed Central ID
PMC3839735
Links
Grant list
R01 NS036853 / NS / NINDS NIH HHS / United States
R56 NS036853 / NS / NINDS NIH HHS / United States
NS036853 / NS / NINDS NIH HHS / United States