TY - JOUR
T1 - SAP102 Mediates Synaptic Clearance of NMDA Receptors
AU - Chen, Bo Shiun
AU - Gray, John A.
AU - Sanz-Clemente, Antonio
AU - Wei, Zhe
AU - Thomas, Eleanor V.
AU - Nicoll, Roger A.
AU - Roche, Katherine W.
N1 - Funding Information:
We thank the NINDS sequencing facility and light imaging facility. We also thank Kenji Sakimura (Niigata University) for the Grin2afl/fl and Grin2bfl/fl mice. The research was supported by the NINDS Intramural Research Program (B.-S.C., A.S.-C., E.V.T., and K.W.R.), a NINDS Career Transition Award (E.V.T., Z.W., and B.-S.C.), grants from the NIMH (J.A.G. and R.A.N.). J.A.G. is funded by a NARSAD Young Investigator Award and is the NARSAD Hammerschlag Family Investigator.
PY - 2012/11/29
Y1 - 2012/11/29
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2012.09.024
DO - 10.1016/j.celrep.2012.09.024
M3 - Article
C2 - 23103165
AN - SCOPUS:84870411807
SN - 2211-1247
VL - 2
SP - 1120
EP - 1128
JO - Cell reports
JF - Cell reports
IS - 5
ER -