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Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation

Abstract

Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide–sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.

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Figure 1: Interaction of Plk2 and NSF.
Figure 2: Plk2 binding disrupts NSF association with GluA2.
Figure 3: Plk2 decreases neuronal surface GluA2.
Figure 4: Plk2 induction is required for activity-dependent decreases in sGluA2.
Figure 5: Plk2 controls GluA2 endocytosis and recycling.
Figure 6: Plk2 effects on sGluA2 are occluded by NSF disruption.
Figure 7: Plk2 binds NSF through a previously unknown interaction motif.
Figure 8: Plk2 binding NSF is sufficient for decreased sGluA2.

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Acknowledgements

We thank L. Bilello for technical assistance. This work was supported by US National Institutes of Health and National Institute of Neurological Disorders and Stroke grants NS048085 (D.T.S.P.), F31NS061467 (D.M.E.) and P30CA051008 (Biacore Molecular Interactions Shared Resource of Lombardi Comprehensive Cancer Center).

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D.M.E., H.-S.H., J.A.M., D.Z. and D.T.S.P. performed experiments. D.M.E., S.H.L., J.T.I. and D.T.S.P. designed the experiments. D.M.E. and D.T.S.P. wrote the manuscript. D.T.S.P. supervised the project.

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Correspondence to Daniel T S Pak.

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Evers, D., Matta, J., Hoe, HS. et al. Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation. Nat Neurosci 13, 1199–1207 (2010). https://doi.org/10.1038/nn.2624

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