Memon Tosifa, Chase Kevin, Leavitt Lee S, Olivera Baldomero M, Teichert Russell W
Department of Biology, University of Utah, 257 S. 1400 E., Salt Lake City, UT 84112, United States.
Department of Biology, University of Utah, 257 S. 1400 E., Salt Lake City, UT 84112, United States.
Neuroscience. 2017 Jun 14;353:76-86. doi: 10.1016/j.neuroscience.2017.04.001. Epub 2017 Apr 10.
The molecular sensor of innocuous (painless) cold sensation is well-established to be transient receptor potential cation channel, subfamily M, member 8 (TRPM8). However, the role of transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in noxious (painful) cold sensation has been controversial. We find that TRPA1 channels contribute to the noxious cold sensitivity of mouse somatosensory neurons, independent of TRPM8 channels, and that TRPA1-expressing neurons are largely non-overlapping with TRPM8-expressing neurons in mouse dorsal-root ganglia (DRG). However, relatively few TRPA1-expressing neurons (e.g., responsive to allyl isothiocyanate or AITC, a selective TRPA1 agonist) respond overtly to cold temperature in vitro, unlike TRPM8-expressing neurons, which almost all respond to cold. Using somatosensory neurons from TRPM8-/- mice and subtype-selective blockers of TRPM8 and TRPA1 channels, we demonstrate that responses to cold temperatures from TRPA1-expressing neurons are mediated by TRPA1 channels. We also identify two factors that affect the cold-sensitivity of TRPA1-expressing neurons: (1) cold-sensitive AITC-sensitive neurons express relatively more TRPA1 transcripts than cold-insensitive AITC-sensitive neurons and (2) voltage-gated potassium (K) channels attenuate the cold-sensitivity of some TRPA1-expressing neurons. The combination of these two factors, combined with the relatively weak agonist-like activity of cold temperature on TRPA1 channels, partially explains why few TRPA1-expressing neurons respond to cold. Blocking K channels also reveals another subclass of noxious cold-sensitive DRG neurons that do not express TRPM8 or TRPA1 channels. Altogether, the results of this study provide novel insights into the cold-sensitivity of different subclasses of somatosensory neurons.
无害（无痛）冷觉的分子传感器已明确为瞬时受体电位阳离子通道M亚家族成员8（TRPM8）。然而，瞬时受体电位阳离子通道A亚家族成员1（TRPA1）在有害（疼痛）冷觉中的作用一直存在争议。我们发现，TRPA1通道对小鼠体感神经元的有害冷敏感性有贡献，且独立于TRPM8通道，并且在小鼠背根神经节（DRG）中，表达TRPA1的神经元与表达TRPM8的神经元在很大程度上不重叠。然而，与几乎所有都对冷有反应的表达TRPM8的神经元不同，相对较少表达TRPA1的神经元（例如，对异硫氰酸烯丙酯或AITC，一种选择性TRPA1激动剂有反应）在体外对冷温度有明显反应。使用来自TRPM8基因敲除小鼠的体感神经元以及TRPM8和TRPA1通道的亚型选择性阻滞剂，我们证明表达TRPA1的神经元对冷温度的反应是由TRPA1通道介导的。我们还确定了影响表达TRPA1的神经元冷敏感性的两个因素：（1）对冷敏感的AITC敏感神经元比不敏感的AITC敏感神经元表达相对更多的TRPA1转录本；（2）电压门控钾（K）通道减弱了一些表达TRPA1的神经元的冷敏感性。这两个因素的组合，再加上冷温度对TRPA1通道相对较弱的激动剂样活性，部分解释了为什么很少有表达TRPA1的神经元对冷有反应。阻断K通道还揭示了另一类对有害冷敏感的DRG神经元，它们不表达TRPM8或TRPA1通道。总之，这项研究的结果为体感神经元不同亚类的冷敏感性提供了新的见解。
