Volume 22 Issue 4, April 2012: 677-696
ORIGINAL ARTICLES
Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons
Xu-Qiao Chen1,*, Bin Wang1,*, Chengbiao Wu2, Jin Pan1, Bo Yuan3, Yuan-Yuan Su1, Xing-Yu Jiang3, Xu Zhang4 and Lan Bao1
1State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, Ca 92093, USA
3National Center of Nanoscience and Technology, Beijing 100190, China
4Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Correspondence: Lan Bao,(baolan@sibs.ac.cn)
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)2X
3 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 P2X
3 receptors into endosomes, while Rab7 mediates the fast retrograde transport of P2X
3 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 P2X
3 receptors. The α, β-MeATP-induced Ca
2+ influx activated a pathway comprised of protein kinase C, rat sarcoma viral oncogene and extracellular signal-regulated protein kinase (ERK), which associated with endocytic P2X
3 receptors to form signaling endosomes. Disruption of the lipid rafts abolished the α, β-MeATP-induced ERK phosphorylation, endocytosis and retrograde transport of P2X
3 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 P2X
3 receptor-activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand-gated channels.
Cell Research (2012) 22:677-696. doi:10.1038/cr.2011.197; published online 13 December 2011
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