TY - JOUR T1 - Activation of UTP-Sensitive P2Y2 Receptor Induces the Expression of Cholinergic Genes in Cultured Cortical Neurons: A Signaling Cascade Triggered by Ca2+ Mobilization and ERK Phosphorylation JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.084160 SP - mol.112.084160 AU - Roy Choi AU - Glanice Chu AU - Nina Siow AU - Amanda Yung AU - Lisa Yung AU - Pinky Lee AU - Christopher Lo AU - Joseph Simon AU - Tina Dong AU - Eric Barnard AU - Karl Tsim Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/04/16/mol.112.084160.abstract N2 - Adenosine 5'-triphosphate (ATP) functions as an extracellular signaling molecule that is co-stored and co-released with neurotransmitters at central and peripheral neuronal synapses. Stimulation by ATP up-regulates the expression of synaptic genes in muscle - including the genes for nicotine acetylcholine receptor (α-, δ- and ϵ-subunits) and acetylcholinesterase (AChE) - via the P2Y receptor (P2YR), but the trophic response of neurons to the activation of P2YRs is less well understood. We reported that cultured cortical neurons and the developing rat brain expressed different types of P2YRs, and among these the UTP-sensitive P2Y2R was the most abundant. P2Y2R was found to exist in membrane rafts and it co-localized with the post-synaptic protein PSD-95 in cortical neurons. Notably, agonist-dependent stimulation of P2Y2R elevated the neuronal expression of cholinergic genes encoding AChE, PRiMA (an anchor for the globular form AChE) and choline acetyltransferase, and this induction was mediated by a signaling cascade that involved Ca2+ mobilization and ERK1/2 activation. The importance of P2Y2R action was further shown by the receptor's synergistic effect with P2Y1R in enhancing cholinergic gene expression via the robust stimulation of Ca2+ influx. Taken together our results revealed a developmental function of P2Y2R in promoting synaptic gene expression and demonstrate the influence of co-stimulation of P2Y1R and P2Y2R in neurons. ER -