GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling

Nat Neurosci. 2012 Dec;15(12):1655-66. doi: 10.1038/nn.3259. Epub 2012 Nov 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Guanine Nucleotide Exchange Factors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Psd protein, rat
  • SAP90-PSD95 Associated Proteins