Proteomic analysis of NMDA receptor-adhesion protein signaling complexes

N-methyl-D-aspartate receptors (NMDAR) mediate long-lasting changes in syna pse strength via downstream signaling pathways. We report proteomic charact erization with mass spectrometry and immunoblotting of NMDAR multiprotein c omplexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins org anized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AM PA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effecter s including MAPK pathway components. Several proteins were encoded by activ ity-dependent genes. Genetic or pharmacological interference with 15 NRC pr oteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2 L1) are associated with learning impairments, indicating the NRC also participates in human cognit ion.