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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1318860110

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

Publication TypeJournal Article
Year of Publication2013
AuthorsLoebrich, S, Djukic, B, Tong, ZJ, Cottrell, JR, Turrigiano, GG, Nedivi, E
JournalProc Natl Acad Sci U S A
Date Published2013 Nov 19
KeywordsActins, Analysis of Variance, Animals, Cloning, Molecular, Cytoskeleton, Endocytosis, Immunohistochemistry, Immunoprecipitation, Lentivirus, Mass Spectrometry, Nerve Tissue Proteins, Nuclear Proteins, Patch-Clamp Techniques, Phosphorylation, Rats, Rats, Long-Evans, Receptors, Glutamate, Synapses

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID24191017
PubMed Central IDPMC3839735
Grant ListR01 NS036853 / NS / NINDS NIH HHS / United States
R56 NS036853 / NS / NINDS NIH HHS / United States
NS036853 / NS / NINDS NIH HHS / United States