Extracellular MicroRNAs Activate Nociceptor Neurons to Elicit Pain via TLR7 and TRPA1
Chul-Kyu Park,1,2 Zhen-Zhong Xu,1,2 Temugin Berta,1,2 Qingjian Han,1 Gang Chen,1 Xing-Jun Liu,1 and Ru-Rong Ji1,* 1Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
2Co-first authors
*Correspondence: ru-rong.ji@duke.edu http://dx.doi.org/10.1016/j.neuron.2014.02.011 Extracellular MicroRNAs Activate Nociceptor neurins to elicit pain via TLR7 and TRPV1
Intracellular microRNAs (miRNAs) are key regulators of gene expression. The role of extracellular miRNAs in neuronal activation and sensory behaviors are unknown. Here we report an unconventional role of extracellular miRNAs for rapid excitation of nocicep- tor neurons via toll-like receptor-7 (TLR7) and its coupling to TRPA1 ion channel. miRNA-let-7b induces rapid inward currents and action potentials in dorsal root ganglion (DRG) neurons. These re- sponses require the GUUGUGU motif, only occur in neurons coexpressing TLR7 and TRPA1, and are abolished in mice lacking Tlr7 or Trpa1. Furthermore, let-7b induces TLR7/TRPA1-dependent single-chan- nel activities in DRG neurons and HEK293 cells over- expressing TLR7/TRPA1. Intraplantar injection of let-7b elicits rapid spontaneous pain via TLR7 and TRPA1. Finally, let-7b can be released from DRG neurons by neuronal activation, and let-7b inhibitor reduces formalin-induced TRPA1 currents and spon- taneous pain. Thus, secreted extracellular miRNAs may serve as novel pain mediators via activating TLR7/TRPA1 in nociceptor neurons.
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Filename : extracellular-micrornas-activate-nociceptor-neurins-to-elicit-pain-via-tlr7-and-trpv1.pdf (2 MB)
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