12月13日，国际著名杂志Cell Research在线发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所鲍岚研究组的研究成果“Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons 。”（P2X3受体信号在初级感觉神经元的轴突中具有逆向转运的特性）。
ATP门控离子通道P2X3选择性地表达于初级感觉神经元，对生理性和病理性疼痛至关重要。传统的观点认为，位于神经末梢的P2X3受体激活后可以引起细胞外的钙离子内流进而引起动作电位的发放，而对于P2X3受体的长距离以及长时程的信号传递的方式及其机制并不十分清楚。
小GTP酶Rab5参与了P2X3受体进入内吞体的过程，Rab7则负责其长距离的逆向转运，P2X3受体的内吞和逆向转运都是受其配体ATP调控的，ATP激活的信号通路分子与内吞的P2X3受体一起进入到内吞体，形成了信号内吞体，神经元膜上的脂筏介导了P2X3受体的内吞和下游信号激活，信号内吞体进一步通过神经元轴突的逆向转运到胞体，调节胞体中转录因子CREB的磷酸化水平，同时影响神经元的兴奋性。
该研究不但证明了感觉神经元中P2X3受体能够逆向运输并以内吞体的形式传递信号，而且提供了一种门控离子通道新的信号传递机制。该项工作由博士研究生陈序谯和王斌等完成。该工作得到了中国科学院、国家自然科学基金、科技部蛋白质重大研究计划等项目的资助。（生物谷Bioon.com）
doi:10.1038/cr.2011.197
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Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons
Xu-Qiao Chen, Bin Wang, Chengbiao Wu, Jin Pan, Bo Yuan, Yuan-Yuan Su, Xing-Yu Jiang, Xu Zhang and Lan Bao
Neurotrophins and their receptors adopt signaling endosomes to transmit retrograde signals. However, the mechanisms of retrograde signaling for other ligand/receptor systems are poorly understood. Here, we report that the signals of the purinergic (P)2X3 receptor, an ATP-gated ion channel, are retrogradely transported in dorsal root ganglion (DRG) neuron axons. We found that Rab5, a small GTPase, controls the early sorting of P2X3 receptors into endosomes, while Rab7 mediates the fast retrograde transport of P2X3 receptors. Intraplantar injection and axonal application into the microfluidic chamber of α, β-methylene-ATP (α, β-MeATP), a P2X selective agonist, enhanced the endocytosis and retrograde transport of P2X3 receptors. The α, β-MeATP-induced Ca2+ influx activated a pathway comprised of protein kinase C, rat sarcoma viral oncogene and extracellular signal-regulated protein kinase (ERK), which associated with endocytic P2X3 receptors to form signaling endosomes. Disruption of the lipid rafts abolished the α, β-MeATP-induced ERK phosphorylation, endocytosis and retrograde transport of P2X3 receptors. Furthermore, treatment of peripheral axons with α, β-MeATP increased the activation level of ERK and cAMP response element-binding protein in the cell bodies of DRG neurons and enhanced neuronal excitability. Impairment of either microtubule-based axonal transport in vivo or dynein function in vitro blocked α, β-MeATP-induced retrograde signals. These results indicate that P2X3 receptor-activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand-gated channels.
