Abstract

ATP functions as an extracellular signaling molecule that is costored and coreleased with neurotransmitters at central and peripheral neuronal synapses. Stimulation by ATP upregulates 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 colocalized with the postsynaptic 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 extracellular regulated kinases 1/2 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 demonstrated the influence of costimulation of P2Y₁R and P2Y₂R in neurons.