TY - JOUR T1 - ATP Induces Synaptic Gene Expressions in Cortical Neurons: Transduction and Transcription Control via P2Y<sub>1</sub> Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1059 LP - 1071 DO - 10.1124/mol.110.066506 VL - 78 IS - 6 AU - Nina L. Siow AU - Roy C. Y. Choi AU - Heidi Q. Xie AU - Ling W. Kong AU - Glanice K. Y. Chu AU - Gallant K. L. Chan AU - Joseph Simon AU - Eric A. Barnard AU - Karl W. K. Tsim Y1 - 2010/12/01 UR - http://molpharm.aspetjournals.org/content/78/6/1059.abstract N2 - 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 P2Y1 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 P2Y1 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 P2Y1 (G-protein-coupled) receptors induced the elevation of intracellular Ca2+ and activation of a mitogen-activated protein kinase/Raf-1 signaling cascade. This led to distinct up-regulation of the genes encoding acetylcholinesterase (AChET variant), choline acetyltransferase, and the N-methyl-d-aspartate receptor subunit NR2A. This was confirmed, in the example of AChE, to arise from P2Y1-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 P2Y1 receptor activation. The combined findings reveal that ATP, via its P2Y1 receptor, can act trophically in brain neurons to regulate the gene expression of direct effectors of synaptic transmission. ER -