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GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling

Nature Neuroscience volume 15, pages 1655–1666 (2012)Cite this article

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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 Ca2+ 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.

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Figure 1: CaMKII activity is required for both Bic-induced removal and TTX-dependent accumulation of GKAP and PSD-95 at synapses.
Figure 2: CaMKII isoform-specific regulation of activity-dependent GKAP turnover.
Figure 3: CaMKII activity is required for the degradation of GKAP by the UPS.
Figure 4: Phosphorylation of GKAP by CaMKII prevents PSD-95 interaction.
Figure 5: Phosphorylation of Ser54 in GKAP induces polyubiquitination and removal of GKAP from synapses.
Figure 6: Role of MVa-DLC and CaMKII phosphorylation in GKAP accumulation at synapses.
Figure 7: GKAP ΔR1 mutant blocks activity-dependent remodeling of PSD proteins.
Figure 8: GKAP turnover is critical for bidirectional homeostatic synaptic scaling.

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Acknowledgements

We thank Q.-S. Liu for technical advice on electrophysiology, and A. Tamada and H. Kamiguchi (RIKEN Brain Science Institute) for providing MyoV expression vectors. This work was supported by US National Institutes of Health grant R01 MH078135 and Whitehall Foundation grant to S.H.L and by US National Institutes of Health grant R01 AG032320 to N.Z.G.

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  1. Morgan Sheng

    Present address: Present address: Department of Neuroscience, Genentech, Inc., South San Francisco, California, USA.,

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Seung Min Shin, Nanyan Zhang, Jonathan Hansen & Sang H Lee

  2. Department of Cell Biology and Neurobiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Nashaat Z Gerges

  3. Department of Pharmacology, Georgetown University Medical Center, Washington, District of Columbia, USA

    Daniel T S Pak

  4. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Morgan Sheng

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Contributions

S.M.S., N.Z., J.H. and S.H.L. conducted all experiments and analyzed the data. N.Z.G., D.T.S.P., M.S. and S.H.L. contributed to designing experiments and interpretation of the data. S.H.L. and M.S. wrote the manuscript.

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Correspondence to Sang H Lee.

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Shin, S., Zhang, N., Hansen, J. et al. GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling. Nat Neurosci 15, 1655–1666 (2012). https://doi.org/10.1038/nn.3259

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