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mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression

Nature Cell Biology volume 7, pages 1179–1190 (2005)Cite this article

An Erratum to this article was published on 02 December 2005

Abstract

Appropriate trafficking and targeting of glutamate receptors (GluRs) to the postsynaptic density is crucial for synaptic function. We show that mPins (mammalian homologue of Drosophila melanogaster partner of inscuteable) interacts with SAP102 and PSD-95 (two PDZ proteins present in neurons), and functions in the formation of the NMDAR–MAGUK (N-methyl-D-aspartate receptor–membrane-associated guanylate kinase) complex. mPins enhances trafficking of SAP102 and NMDARs to the plasma membrane in neurons. Expression of dominant–negative constructs and short-interfering RNA (siRNA)-mediated knockdown of mPins decreases SAP102 in dendrites and modifies surface expression of NMDARs. mPins changes the number and morphology of dendritic spines and these effects depend on its Gαi interaction domain, thus implicating G-protein signalling in the regulation of postsynaptic structure and trafficking of GluRs.

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Figure 1: mPins interacts with SAP102 and MAGUK proteins.
Figure 2: NMDAR and SAP102 coimmunoprecipitate with mPins in brain.
Figure 3: Interactions of mPins and SAP102 in heterologous cells.
Figure 4: NR2B is associated with SAP102 and mPins early in the secretory pathway.
Figure 5: Postsynaptic targeting of mPins and SAP102 in hippocampal neurons.
Figure 6: Targeting of mPins mutants in hippocampal neurons.
Figure 7: siRNAs knock down mPins expression and reduce surface expression of Flag–NR2B.
Figure 8: The Gαi–mPins complex functions in trafficking of NR2B in hippocampal neurons.

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Acknowledgements

We thank C.C. Garner for providing the SAP102 cDNA, D. Bredt for the PSD-95 and PSD-95 C3,5S GFP-tagged constructs, A. El-Husseini for the GKAP construct, D.B. Arnold for the Kv1.4 construct, A. Stephenson for the Flag-tagged NR2B construct, K.W. Roche for the Tac constructs, and J. Hell for the SAP102 antibody. We thank K. Prybylowski and L.A. Dunbar for discussion and helpful suggestions. We also thank M. Montcouquiol and S. M. Lanier for valuable comments on the manuscript. Animals were handled in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals. Supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), NIH grant GM070902 to I.M., and NIH grant F32MH65092 to J.B.

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Author notes

  1. Nathalie Sans

    Present address: Equipe AVENIR, IFR8, Institut National de la Sante et de la Recherche Medicale, Institut des Neurosciences F. Magendie, 33077, Bordeaux Cedex, France

Authors and Affiliations

  1. Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 50, Room 4146, 50 South Drive, Bethesda, 20892-8027, MD, USA

    Nathalie Sans, Philip Y. Wang, Ronald S. Petralia, Ya-Xian Wang, Sajan Nakka & Robert J. Wenthold

  2. Center for Cell Signaling and Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, 22908, VA, USA

    Quansheng Du & Ian G. Macara

  3. Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, 1901 Perdido St., P7-1, New Orleans, 70112, LA, USA

    Joe B. Blumer

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Sans, N., Wang, P., Du, Q. et al. mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nat Cell Biol 7, 1179–1190 (2005). https://doi.org/10.1038/ncb1325

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