Neurotransmitters drive combinatorial multistate postsynaptic density networks.
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.
Coba
Marcelo P
MP
Genes to Cognition, Wellcome Trust Sanger Institute, Cambridgeshire, UK.
Pocklington
Andrew J
AJ
Collins
Mark O
MO
Kopanitsa
Maksym V
MV
Uren
Rachel T
RT
Swamy
Sajani
S
Croning
Mike D R
MD
Choudhary
Jyoti S
JS
Grant
Seth G N
SG
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002853:Chromatography, Liquid; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D040081:Protein Array Analysis; D011485:Protein Binding; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D010750:Phosphoproteins; D020543:Proteome; D017981:Receptors, Neurotransmitter; D016202:N-Methylaspartate