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Neurotransmitters Drive Combinatorial Multistate Postsynaptic Density Networks

Analysis of protein phosphorylation patterns provides insight into the organization of molecular networks at the postsynaptic density. Patterning Postsynaptic Phosphorylation The postsynaptic density of excitatory synapses in the mammalian brain—the initial site for integration of incoming information from the presynaptic neuron—contains over a thousand different proteins. Rather than investigating the effects of neurotransmitter signaling on a single pathway, Coba et al. explored the functional organization of these postsynaptic density proteins. Using a large-scale proteomic approach, they found that stimulation of different classes of neurotransmitter receptor affected the phosphorylation status of hundreds of phosphorylation sites in overlapping networks of postsynaptic density proteins. Identification of a set of regulatory phosphorylation motifs enabled them to construct a model of the molecular circuitry of the postsynaptic proteome, a crucial step in elucidating how postsynaptic neurons process incoming information. The mammalian postsynaptic density (PSD) comprises a complex collection of ~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.