title: Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons.
abstract: 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.
authors.affiliation: State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xu-Qiao
authors.initials: XQ
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Pan
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Su
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Bao
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058477:Receptors, Purinergic P2X3 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008024:Ligands; D058477:Receptors, Purinergic P2X3; D011493:Protein Kinase C