ATP and UTP Excite Sensory Neurons and Induce CREB Phosphorylation Through the Metabotropic Receptor, P2Y2

Extracellular ATP rapidly excites nociceptive sensory neurons by opening ATP-gated ion channels (P2X receptors). Here, we describe two actions of both ATP and UTP on rat sensory neurons that are relatively slow and sustained: phosphorylation of the transcription factor CREB and delayed action potential firing that persists for tens of seconds after removal of the ligand. The pharmacology of these responses indicates that they are mediated by the metabotropic receptor P2Y2, and not by P2X receptors. CREB phosphorylation occurred in a subset of small peripherin-positive neurons likely to be unmyelinated nociceptors. In situ hybridization analysis revealed widespread expression of P2Y2 mRNA in sensory neurons. CREB phosphorylation is mediated by both action-potential-evoked calcium influx and calcium release from intracellular stores. These findings suggest that P2Y2 contributes to the transduction of ATP-mediated sensory signalling, and may be involved in the activity-dependent regulation of nociceptor phenotype.