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GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling. Nat Neurosci 2012 Dec;15(12):1655-66

Date

11/13/2012

Pubmed ID

23143515

Pubmed Central ID

PMC3804128

DOI

10.1038/nn.3259

Scopus ID

2-s2.0-84870494059 (requires institutional sign-in at Scopus site)   101 Citations

Abstract

How does chronic activity modulation lead to global remodeling of proteins at synapses and synaptic scaling? Here we report that guanylate kinase-associated protein (GKAP; also known as SAPAP), a scaffolding molecule linking NMDA receptor-PSD-95 to Shank-Homer complexes, acts in these processes. Overexcitation removes GKAP from synapses via the ubiquitin-proteasome system, whereas inactivity induces synaptic accumulation of GKAP in rat hippocampal neurons. Bidirectional changes in synaptic GKAP amounts are controlled by specific CaMKII isoforms coupled to different Ca(2+) channels. CaMKII╬▒ activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP. In contrast, CaMKII╬▓ activation via L-type voltage-dependent calcium channels promotes GKAP recruitment by phosphorylating GKAP Ser340 and Ser384, which uncouples GKAP from myosin Va motor complex. Overexpressing GKAP turnover mutants not only hampers activity-dependent remodeling of PSD-95 and Shank but also blocks bidirectional synaptic scaling. Therefore, activity-dependent turnover of PSD proteins orchestrated by GKAP is critical for homeostatic plasticity.

Author List

Shin SM, Zhang N, Hansen J, Gerges NZ, Pak DT, Sheng M, Lee SH

Authors

Nashaat Gerges PhD Chair, Professor in the School of Pharmacy Administration department at Medical College of Wisconsin
Sang H. Lee PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
COS Cells
Cells, Cultured
Disks Large Homolog 4 Protein
Double-Blind Method
Enzyme Activation
Guanine Nucleotide Exchange Factors
Homeostasis
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Nerve Tissue Proteins
Neuronal Plasticity
Rats
SAP90-PSD95 Associated Proteins
Synapses
Synaptic Potentials