title: GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling.
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. CaMKIIα activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP. In contrast, CaMKIIβ 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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Seung Min
authors.initials: SM
authors.lastname: Shin
authors.forename: Nanyan
authors.initials: N
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hansen
authors.forename: Nashaat Z
authors.initials: NZ
authors.lastname: Gerges
authors.forename: Daniel T S
authors.initials: DT
authors.lastname: Pak
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
authors.forename: Sang H
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000076122:Disks Large Homolog 4 Protein; D004311:Double-Blind Method; D004789:Enzyme Activation / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D000074407:SAP90-PSD95 Associated Proteins; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C504475:Psd protein, rat; D000074407:SAP90-PSD95 Associated Proteins