Pocklington, A.J., Cumiskey, M., Armstrong, J.D. & Grant, S.G.N. The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behavior. Mol. Syst. Biol. 2, E1-E14

School of Informatics, Edinburgh University, Edinburgh, UK.
Molecular Systems Biology (Impact Factor: 10.87). 02/2006; 2(1):2006.0023. DOI: 10.1038/msb4100041
Source: PubMed


Neuronal synapses play fundamental roles in information processing, behaviour and disease. Neurotransmitter receptor complexes, such as the mammalian N-methyl-D-aspartate receptor complex (NRC/MASC) comprising 186 proteins, are major components of the synapse proteome. Here we investigate the organisation and function of NRC/MASC using a systems biology approach. Systematic annotation showed that the complex contained proteins implicated in a wide range of cognitive processes, synaptic plasticity and psychiatric diseases. Protein domains were evolutionarily conserved from yeast, but enriched with signalling domains associated with the emergence of multicellularity. Mapping of protein-protein interactions to create a network representation of the complex revealed that simple principles underlie the functional organisation of both proteins and their clusters, with modularity reflecting functional specialisation. The known functional roles of NRC/MASC proteins suggest the complex co-ordinates signalling to diverse effector pathways underlying neuronal plasticity. Importantly, using quantitative data from synaptic plasticity experiments, our model correctly predicts robustness to mutations and drug interference. These studies of synapse proteome organisation suggest that molecular networks with simple design principles underpin synaptic signalling properties with important roles in physiology, behaviour and disease.

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    • "Over the last decade the identification of synaptic proteins using mass spectrometry has transformed the view of the synapse as a relatively simple structure to one with a high degree of molecular complexity [1]. Proteomic studies from fly [2], mouse [3], [4], rat [5], [6] and human [7], [8] have identified many hundreds of postsynaptic proteins that are organized through physical interactions into multiprotein complexes and networks [9]. The overall function of these structures is to mediate the contact and communication of information between nerve cells. "
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    • "How do we merge this understanding with current systems biology models of molecular cognition? A number of recent studies have modeled the synaptic proteome focusing on its composition and function, typically representing the relationships between members in protein– protein interaction networks (PINs) where network membership is determined by proteomic profile and connectivity by the propensity for constituent proteins to physically interact in vitro (Collins et al. 2006; Pocklington et al. 2006; Fernandez et al. 2009). These networks have been used to dissect out functional modules of the postsynaptic density, map disease associations, and assess the evolutionary conservation of function. "
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