Neurotransmitters Drive Combinatorial Multistate Postsynaptic Density Networks

Sci. Signal., 28 April 2009
Vol. 2, Issue 68, p. ra19
DOI: 10.1126/scisignal.2000102

Neurotransmitters Drive Combinatorial Multistate Postsynaptic Density Networks

  1. Marcelo P. Coba1,
  2. Andrew J. Pocklington2,
  3. Mark O. Collins3,
  4. Maksym V. Kopanitsa1,
  5. Rachel T. Uren1,
  6. Sajani Swamy3,
  7. Mike D. R. Croning1,
  8. Jyoti S. Choudhary3, and
  9. Seth G. N. Grant1,*
  1. 1Genes to Cognition, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
  2. 2Institute for Adaptive and Neural Computation, Division of Informatics, University of Edinburgh, 5 Forrest Hill, Edinburgh EH1 2QL, UK.
  3. 3Proteomic Mass Spectrometry, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
  1. *To whom correspondence should be addressed. E-mail: sg3{at}sanger.ac.uk

Abstract

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.

Citation:

M. P. Coba, A. J. Pocklington, M. O. Collins, M. V. Kopanitsa, R. T. Uren, S. Swamy, M. D. Croning, J. S. Choudhary, and S. G. Grant, Neurotransmitters Drive Combinatorial Multistate Postsynaptic Density Networks. Sci. Signal. 2, ra19 (2009).

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