Article

Synaptic clustering of PSD-95 is regulated by c-Abl through tyrosine phosphorylation.

Laboratorio de Señalización Celular, Departmento de Biología Celular y Molecular, Pontificia Universidad Católica de Chile, 8331010 Santiago, Chile.
Journal of Neuroscience (impact factor: 7.11). 03/2010; 30(10):3728-38. DOI:10.1523/JNEUROSCI.2024-09.2010 pp.3728-38
Source: PubMed

ABSTRACT The c-Abl tyrosine kinase is present in mouse brain synapses, but its precise synaptic function is unknown. We found that c-Abl levels in the rat hippocampus increase postnatally, with expression peaking at the first postnatal week. In 14 d in vitro hippocampal neuron cultures, c-Abl localizes primarily to the postsynaptic compartment, in which it colocalizes with the postsynaptic scaffold protein postsynaptic density protein-95 (PSD-95) in apposition to presynaptic markers. c-Abl associates with PSD-95, and chemical or genetic inhibition of c-Abl kinase activity reduces PSD-95 tyrosine phosphorylation, leading to reduced PSD-95 clustering and reduced synapses in treated neurons. c-Abl can phosphorylate PSD-95 on tyrosine 533, and mutation of this residue reduces the ability of PSD-95 to cluster at postsynaptic sites. Our results indicate that c-Abl regulates synapse formation by mediating tyrosine phosphorylation and clustering of PSD-95.

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  • Article: Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function.
    Oliver M Schlüter, Weifeng Xu, Robert C Malenka
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    ABSTRACT: PSD-95 and SAP97 are scaffolding proteins that have been implicated in regulating AMPA receptor incorporation and function at synapses. Gain- and loss-of-function approaches, however, have generated conflicting results. To minimize adaptations during development and potential dominant-negative effects of overexpression, we have combined silencing of endogenous PSD-95 in mature neurons with heterologous expression of specific SAP97 or PSD-95 isoforms. We find that both PSD-95 and SAP97 contain alternative N termini expressing either double cysteines that normally are palmitoylated (alpha-isoforms) or an L27 domain (beta-isoforms). Whereas alpha-isoforms of PSD-95 and SAP97 influence AMPA receptor-mediated synaptic strength independent of activity, the effects of beta-isoforms are regulated by activity in a CaMKII-dependent manner. Importantly, the synaptic effects of the beta-isoforms are masked by the endogenous alpha-isoform of PSD-95. These results demonstrate that the different N termini of the predominant endogenous forms of PSD-95 (alpha-isoform) and SAP97 (beta-isoform) govern their role in regulating synaptic function.
    Neuron 08/2006; 51(1):99-111. · 14.74 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

c-Abl
 
c-Abl associates
 
c-Abl kinase activity
 
c-Abl levels
 
c-Abl localizes
 
c-Abl regulates synapse formation
 
c-Abl tyrosine kinase
 
first postnatal week
 
genetic inhibition
 
mediating tyrosine phosphorylation
 
mouse brain synapses
 
mutation
 
postsynaptic compartment
 
postsynaptic scaffold protein postsynaptic density protein-95
 
postsynaptic sites
 
presynaptic markers
 
rat hippocampus increase postnatally
 
synapses