Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Pain Signaling and Plasticity Laboratory, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Neuron. 2014 Apr 2;82(1):47-54. doi: 10.1016/j.neuron.2014.02.011.
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 nociceptor 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 responses 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-channel activities in DRG neurons and HEK293 cells overexpressing 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 spontaneous pain. Thus, secreted extracellular miRNAs may serve as novel pain mediators via activating TLR7/TRPA1 in nociceptor neurons.
细胞内 microRNAs (miRNAs) 是基因表达的关键调节因子。细胞外 miRNAs 在神经元激活和感觉行为中的作用尚不清楚。在这里，我们报告了细胞外 miRNAs 通过 Toll 样受体 7 (TLR7) 及其与 TRPA1 离子通道偶联，对伤害感受器神经元快速兴奋的非传统作用。miRNA-let-7b 在背根神经节 (DRG) 神经元中诱导快速内向电流和动作电位。这些反应需要 GUUGUGU 基序，仅发生在共表达 TLR7 和 TRPA1 的神经元中，并且在缺乏 Tlr7 或 Trpa1 的小鼠中被消除。此外，let-7b 在过表达 TLR7/TRPA1 的 DRG 神经元和 HEK293 细胞中诱导 TLR7/TRPA1 依赖性单通道活性。足底注射 let-7b 通过 TLR7 和 TRPA1 引发快速自发性疼痛。最后，DRG 神经元激活时可以释放 let-7b，let-7b 抑制剂可减少福尔马林诱导的 TRPA1 电流和自发性疼痛。因此，分泌的细胞外 miRNAs 可能通过激活伤害感受器神经元中的 TLR7/TRPA1 而作为新型疼痛介质。
