title: ATP induces synaptic gene expressions in cortical neurons: transduction and transcription control via P2Y1 receptors.
abstract: 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.
authors.affiliation: Department of Biology and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China.
authors.forename: Nina L
authors.initials: NL
authors.lastname: Siow
authors.forename: Roy C Y
authors.initials: RC
authors.lastname: Choi
authors.forename: Heidi Q
authors.initials: HQ
authors.lastname: Xie
authors.forename: Ling W
authors.initials: LW
authors.lastname: Kong
authors.forename: Glanice K Y
authors.initials: GK
authors.lastname: Chu
authors.forename: Gallant K L
authors.initials: GK
authors.lastname: Chan
authors.forename: Joseph
authors.initials: J
authors.lastname: Simon
authors.forename: Eric A
authors.initials: EA
authors.lastname: Barnard
authors.forename: Karl W K
authors.initials: KW
authors.lastname: Tsim
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000235:genetics* / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D058851:GPI-Linked Proteins; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate; C548244:ACHE protein, human; D000110:Acetylcholinesterase