上海科技大学知识管理系统

The P2X3 receptor plays a vital role in sensory processing and transmission. The assembly and trafficking of the P2X3 receptor are important for its function in primary sensory neurons. As an important inflammation mediator, ATP is released from different cell types around primary sensory neurons, especially under pathological pain conditions. Here, we show that a, alpha,beta-MeATP dramatically promoted membrane delivery of the P2X3 receptor both in HEK293T cells expressing recombinant P2X3 receptor and in rat primary sensory neurons. alpha, beta-MeATP induced P2X3 receptor-mediated Ca2+ influx, which further activated Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha). The N terminus of the P2X3 receptor was responsible for CaMKIIa binding, whereas Thr(388) in the C terminus was phosphorylated by CaMKII alpha. Thr(388) phosphorylation increased P2X3 receptor binding to caveolin-1. Caveolin-1 knockdown abrogated the alpha, beta-MeATP-induced membrane insertion of the P2X3 receptor. Moreover, alpha,beta-MeATP drove the CaMKII alpha-mediated membrane coinsertion of the P2X2 receptor with the P2X3 receptor. The increased P2X3 receptors on the cell membrane that are due to Thr(388) phosphorylation facilitated P2X3 receptor-mediated signal transduction. Together, our data indicate that CaMKII alpha and caveolin-1 cooperate to drive ligand-induced membrane delivery of the P2X3 receptor and may provide a mechanism of P2X3 receptor sensitization in pain development.