Proteomic analysis of NMDA receptor-adhesion protein signaling complexes

• Published in: Nature neuroscience Vol. 3; no. 7; pp. 661 - 669
• Main Authors: Grant, Seth G. N, Husi, Holger, Ward, Malcolm A, Choudhary, Jyoti S, Blackstock, Walter P
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2000
• Subjects: Adaptor proteins; Adhesion; Animals; Brain - physiology; Brain research; Cadherins - chemistry; Cadherins - physiology; Cell adhesion; Cell adhesion molecules; Cell receptors; Cognition; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - physiology; Cytoskeleton; Genes; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Glutamic acid receptors (metabotropic); Humans; Immunoblotting; Kinases; Learning; MAP kinase; Mass Spectrometry; Mass spectroscopy; Methyl aspartate; Mice; Mutation; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurosciences; Neurotransmitter Agents - chemistry; Neurotransmitter Agents - physiology; Neurotransmitters; Peptides; Phosphatase; Physiological aspects; Protein Kinases - chemistry; Protein Kinases - metabolism; Proteins; Proteomics; R&D; Receptors; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - physiology; Research & development; Scientific imaging; Signal transduction; Signal Transduction - physiology; Signaling; Synapses; Synaptic plasticity; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; United Kingdom
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/76615

N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized 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 AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins 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 cognition.