Endosome-Mediated Retrograde Axonal Transport of P2X3 Receptor Signals in Primary Sensory Neurons

The ATP-gated ion channel P2X₃ receptor, which is abundantly expressed in primary sensory neurons, plays an important role in inflammation and neuropathic pain. It is well established that P2X₃ receptor after activation at the nerve terminal can induce extracellular calcium influx and action potential, but the mode and mechanism for the long-distance and long-term signal transduction of P2X₃ receptor remains to be defined. A group of researchers, led by BAO Lan, at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, provided the first evidence that the signal of P2X₃ receptor can be retrogradely transported from the terminals to the cell bodies in the axons of primary sensory neurons via “signaling endosome”.

 

CHEN Xuqiao and WANG Bin, under the supervision of Dr. BAO Lan, used a series of in vivo, in vitro and ex vivo experiments to confirm the retrograde transport of P2X₃ receptor signal. Small GTPase Rab7 mediated the long-distance retrograde axonal transport and Rab5 is required during a step that precedes this transport. Both the endocytosis and retrograde transport of P2X₃ receptor were ligand dependent. The downstream signal molecules of P2X₃ receptor could be sorted with endocytic P2X₃ receptor to the same endosome to form “signaling endosome”, which was retrogradely transported to the cell bodies of primary sensory neurons to regulate the activation level of transcription factor CREB and neuronal excitability. Further research found that lipid rafts mediated both the endocytosis and downstream signal pathway activation of P2X₃ receptor. This research not only demonstrates that P2X₃ receptor can transmit downstream signal retrogradely in a form of “signaling endosome”, but also supplies a new signal transduction mechanism for ligand-gated ion channel.

 

This work entitled “Endosome-mediated retrograde axonal transport of P2X₃ receptor signals in primary sensory neurons” was published on line in Cell Research on Dec 13^th , 2011.

 

This study was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology, National Natural Science Foundation of China. (SIBCB)

 

AUTHOR CONTACT:

BAO Lan

Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Shanghai, China

Phone:86-21-54921369; E-mail: baolan@sibs.ac.cn

 

Retrogradely transported P2X₃ receptors are carried by late endosomes. mRFP-P2X₃-Myc-positive puncta containing GFP-Rab7^WT, but not GFP-Rab5^WT, displayed long-distance retrograde transport in live cell imaging (arrows). However, both dominant-negative Rab7 and Rab5 mutants disrupted the retrograde movement of most mRFP-P2X₃-Myc-positive puncta. Scale bar, 5 μm.
(Image provided by Dr. BAO Lan)