RGD Reference Report - ATP induces synaptic gene expressions in cortical neurons: transduction and transcription control via P2Y1 receptors. - Rat Genome Database

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ATP induces synaptic gene expressions in cortical neurons: transduction and transcription control via P2Y1 receptors.

Authors: Siow, NL  Choi, RC  Xie, HQ  Kong, LW  Chu, GK  Chan, GK  Simon, J  Barnard, EA  Tsim, KW 
Citation: Siow NL, etal., Mol Pharmacol. 2010 Dec;78(6):1059-71. doi: 10.1124/mol.110.066506. Epub 2010 Sep 16.
RGD ID: 8554370
Pubmed: (View Article at PubMed) PMID:20847060
DOI: Full-text: DOI:10.1124/mol.110.066506

Studies in vertebrate neuromuscular synapses have revealed previously that ATP, via P2Y receptors, plays a critical role in regulating postsynaptic gene expressions. An equivalent regulatory role of ATP and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses, but we provide evidence here for a brain version of that role. In cultured cortical neurons, the expression of P2Y(1) receptors increased sharply during neuronal differentiation. Those receptors were found mainly colocalized with the postsynaptic scaffold postsynaptic density protein 95 (PSD-95). This arises through a direct interaction of a PDZ domain of PSD-95 with the C-terminal PDZ-binding motif, D-T-S-L of the P2Y(1) receptor, confirmed by the full suppression of the colocalization upon mutation of two amino acids therein. This interaction is effective in recruiting PSD-95 to the membrane. Specific activation of P2Y(1) (G-protein-coupled) receptors induced the elevation of intracellular Ca(2+) and activation of a mitogen-activated protein kinase/Raf-1 signaling cascade. This led to distinct up-regulation of the genes encoding acetylcholinesterase (AChE(T) variant), choline acetyltransferase, and the N-methyl-d-aspartate receptor subunit NR2A. This was confirmed, in the example of AChE, to arise from P2Y(1)-dependent stimulation of a human ACHE gene promoter. That involved activation of the transcription factor Elk-1; mutagenesis of the ACHE promoter revealed that Elk-1 binding at its specific responsive elements in that promoter was induced by P2Y(1) receptor activation. The combined findings reveal that ATP, via its P2Y(1) receptor, can act trophically in brain neurons to regulate the gene expression of direct effectors of synaptic transmission.

Objects Annotated

Genes (Rattus norvegicus)
Dlg4  (discs large MAGUK scaffold protein 4)
Grin2a  (glutamate ionotropic receptor NMDA type subunit 2A)
P2ry1  (purinergic receptor P2Y1)

Additional Information