RESUMEN

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 Ca(2+) 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 Ca(2+) 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.

Asunto(s)

Calcio/metabolismo , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Uridina Trifosfato/metabolismo , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Animales , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Colina O-Acetiltransferasa/genética , Colina O-Acetiltransferasa/metabolismo , Homólogo 4 de la Proteína Discs Large , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Fosforilación/efectos de los fármacos , Agonistas del Receptor Purinérgico P2Y/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y1/genética , Receptores Purinérgicos P2Y1/metabolismo , Receptores Purinérgicos P2Y2/genética , Transducción de Señal/efectos de los fármacos