Neurotransmitters Drive Combinatorial Multistate Postsynaptic Density Networks

Genes to Cognition, Wellcome Trust Sanger Institute, Cambridgeshire, UK.
Science Signaling (Impact Factor: 6.28). 02/2009; 2(68):ra19. DOI: 10.1126/scisignal.2000102
Source: PubMed


The mammalian postsynaptic density (PSD) comprises a complex collection of approximately 1100 proteins. Despite extensive knowledge of individual proteins, the overall organization of the PSD is poorly understood. Here, we define maps of molecular circuitry within the PSD based on phosphorylation of postsynaptic proteins. Activation of a single neurotransmitter receptor, the N-methyl-D-aspartate receptor (NMDAR), changed the phosphorylation status of 127 proteins. Stimulation of ionotropic and metabotropic glutamate receptors and dopamine receptors activated overlapping networks with distinct combinatorial phosphorylation signatures. Using peptide array technology, we identified specific phosphorylation motifs and switching mechanisms responsible for the integration of neurotransmitter receptor pathways and their coordination of multiple substrates in these networks. These combinatorial networks confer high information-processing capacity and functional diversity on synapses, and their elucidation may provide new insights into disease mechanisms and new opportunities for drug discovery.

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    • "Compared with microarray based screening and phage display system, the mass spectrometry not only identifies phosphoproteins, but also pinpoints their phosphosites. There have been increasing attempts to develop mass spectrometrybased proteomic strategies for the kinase substrates exploration (Huang et al., 2007; Amanchy et al., 2008; Coba et al., 2009). "
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