SAP102 Mediates Synaptic Clearance of NMDA Receptors
Bo-Shiun Chen,
John A. Gray,
Antonio Sanz-Clemente,
Zhe Wei,
Eleanor V. Thomas,
Roger A. Nicoll,
Katherine W. Roche
Affiliations
Bo-Shiun Chen
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
John A. Gray
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
Antonio Sanz-Clemente
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Zhe Wei
Department of Neurology and Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA
Eleanor V. Thomas
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Roger A. Nicoll
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
Katherine W. Roche
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Membrane-associated guanylate kinases (MAGUKs) are the major family of scaffolding proteins at the postsynaptic density. The PSD-MAGUK subfamily, which includes PSD-95, PSD-93, SAP97, and SAP102, is well accepted to be primarily involved in the synaptic anchoring of numerous proteins, including N-methyl-D-aspartate receptors (NMDARs). Notably, the synaptic targeting of NMDARs depends on the binding of the PDZ ligand on the GluN2B subunit to MAGUK PDZ domains, as disruption of this interaction dramatically decreases NMDAR surface and synaptic expression. We recently reported a secondary interaction between SAP102 and GluN2B, in addition to the PDZ interaction. Here, we identify two critical residues on GluN2B responsible for the non-PDZ binding to SAP102. Strikingly, either mutation of these critical residues or knockdown of endogenous SAP102 can rescue the defective surface expression and synaptic localization of PDZ binding-deficient GluN2B. These data reveal an unexpected, nonscaffolding role for SAP102 in the synaptic clearance of GluN2B-containing NMDARs.
