12月13日,，國際著名雜志Cell Research在線發(fā)表了中國科學(xué)院上海生命科學(xué)研究院生物化學(xué)與細(xì)胞生物學(xué)研究所鮑嵐研究組的研究成果“Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons ,。”（P2X3受體信號在初級感覺神經(jīng)元的軸突中具有逆向轉(zhuǎn)運(yùn)的特性）,。
ATP門控離子通道P2X3選擇性地表達(dá)于初級感覺神經(jīng)元,，對生理性和病理性疼痛至關(guān)重要,。傳統(tǒng)的觀點(diǎn)認(rèn)為,，位于神經(jīng)末梢的P2X3受體激活后可以引起細(xì)胞外的鈣離子內(nèi)流進(jìn)而引起動作電位的發(fā)放,，而對于P2X3受體的長距離以及長時程的信號傳遞的方式及其機(jī)制并不十分清楚。
小GTP酶Rab5參與了P2X3受體進(jìn)入內(nèi)吞體的過程,，Rab7則負(fù)責(zé)其長距離的逆向轉(zhuǎn)運(yùn),，P2X3受體的內(nèi)吞和逆向轉(zhuǎn)運(yùn)都是受其配體ATP調(diào)控的，ATP激活的信號通路分子與內(nèi)吞的P2X3受體一起進(jìn)入到內(nèi)吞體,，形成了信號內(nèi)吞體,，神經(jīng)元膜上的脂筏介導(dǎo)了P2X3受體的內(nèi)吞和下游信號激活，信號內(nèi)吞體進(jìn)一步通過神經(jīng)元軸突的逆向轉(zhuǎn)運(yùn)到胞體,，調(diào)節(jié)胞體中轉(zhuǎn)錄因子CREB的磷酸化水平,，同時影響神經(jīng)元的興奮性。
該研究不但證明了感覺神經(jīng)元中P2X3受體能夠逆向運(yùn)輸并以內(nèi)吞體的形式傳遞信號,，而且提供了一種門控離子通道新的信號傳遞機(jī)制,。該項工作由博士研究生陳序譙和王斌等完成,。該工作得到了中國科學(xué)院、國家自然科學(xué)基金,、科技部蛋白質(zhì)重大研究計劃等項目的資助,。（生物谷Bioon.com）
doi:10.1038/cr.2011.197
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PMID:
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.
