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Competition in the postsynaptic density for PDZ domains of PSD-95

Mastro, T. and Preza, A. and Kind, P. and Kennedy, M. B. (2017) Competition in the postsynaptic density for PDZ domains of PSD-95. Molecular Biology of the Cell, 28 (26). Art. No. P3216. ISSN 1059-1524. doi:10.1091/mbc.E17-10-0618.

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Molecular mechanisms of synaptic plasticity are of great interest because derangement of synaptic plasticity contributes to neural diseases such as autism, schizophrenia, cognitive impairment, neuropathic pain, epilepsy, and stroke. This work addresses the molecular mechanisms underlying NMDA‐type glutamate receptor‐triggered plasticity at excitatory synapses. A critical step in this process is a change in the rate of trapping of AMPA‐type receptors (AMPARs) in the postsynaptic density (PSD), which increases the number of AMPARs and strengthens the electrical signal at the synapse. Our work aims to determine whether trapping of AMPARs in the PSD is mediated by rearrangement of the PSD scaffold caused by changes in the affinity of different PSD proteins for the PDZ domains of the major synaptic scaffold protein, PSD‐95. Our earlier publication (1) supports this notion by showing that: 1. Phosphorylation of the abundant PSD protein synGAP by CaMKII reduces its affinity for the PDZ domains of PSD‐95; and 2. The composition of the PSD is altered in synGAP deficient mice such that AMPAR-binding proteins with PDZ ligands, including TARPs and LRRTM2, are increased in concentration relative to PSD‐95. We have now replicated these finding in synGAP‐deficient rats. These findings suggest that the extent of binding of particular synaptic proteins to the PDZ domains of PSD‐95 is regulated by activity‐dependent phosphorylation of synGAP. We are testing this hypothesis in cultured rat neurons. We have isolated PSDs from neuronal cultures before and after induction of synGAP phosphorylation by pharmacological activation of NMDARs. The ratios of AMPAR‐associated proteins to PSD‐95 in the PSDs are determined by quantitative immunoblotting. We have found that the ratio of TARPs to PSD‐95 is consistently increased in PSDs after chemical activation of synaptic NMDARs. We are using cultures from synGAP‐deficient rats to determine if synGAP deficiency alters the composition of the PSD in rat cultures. We plan to transfect with a variety of synGAP mutant proteins in order to determine which domains or phosphorylation sites on synGAP are important for regulating PSD composition.

Item Type:Article
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URLURL TypeDescription
Mastro, T.0000-0003-1302-9753
Kind, P.0000-0002-4256-9639
Kennedy, M. B.0000-0003-1369-0525
Additional Information:© 2017 American Society for Cell Biology. Free via Creative Commons 2 months after publication.
Issue or Number:26
Record Number:CaltechAUTHORS:20180321-145303826
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85406
Deposited By: Tony Diaz
Deposited On:26 Mar 2018 21:32
Last Modified:15 Nov 2021 20:28

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