Molecular elucidation and medical significance of redox-sensitive TRP channels in inflammatory cell infiltration.

活性氧簇(ROS)诱导趋化因子，负责在损伤或感染的炎症部位募集炎性细胞。在这里，我们证明质膜Ca^2通透通道TRPM2控制ROS诱导的单核细胞趋化因子的产生。TRPM2Ca^2内流控制ROS诱导的信号级联反应，后者负责趋化因子的产生，从而加剧炎症。另一方面，氧(O_2)的摄入受到严格的控制，以确保能量的产生，同时将好氧生物的氧化损伤风险降至最低。哺乳动物的呼吸系统已经进化为通过颈动脉小体和其他化学感受器对氧气供应的变化做出反应。在这里，我们对表达在小鼠迷走神经化学感受器上的Trp阳离子通道的功能检测表明，TRPA1通道被O2激活，并通过其对半胱氨酸介导的氧化的显著敏感性来调节高氧条件下的离子电流。在低氧条件下，TRPA1也被激活，这是通过解除Pro_2依赖的羟化酶的抑制而实现的。高氧和低氧诱导的迷走神经传入神经活动和随后的呼吸反应受TRPA1控制。因此，TRPA1是体内调节氧气供应的氧气感受器。

Reactive oxygen species(ROS) induce chemokines responsible for the recruitment of inflammatory cells at inflamed sites in injury or infection. Here, we demonstrate that the plasma membrane Ca^2-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. TRPM2 Ca^2 influx controls the ROS-induced signal cascade responsible for chemokine production which aggravates inflammation. On the other hand, Oxygen(O_2) intake is tightly controlled in order to secure energy production while minimizing the risk of oxidative damage in aerobic organisms. Mammals' respiratory systems have evolved to respond to changes in O_2 availability via the carotid body and other chemoreceptors. Here, our functional examination of the TRP cation channels expressed in mouse vagal chemoreceptors reveals that the TRPA1 channel is activated by O2 and mediates ionic currents in hyperoxia via its prominent sensitivity to cysteine-mediated oxidation. TRPA1 is also activated in hypoxia through relief from O_2-dependent inhibition by prolyl hydroxylases. Hyperoxia-and hypoxia-induced vagal afferent nerve activities and their consequent ventilatory responses are are controlled by TRPA1. Thus, TRPA1 is an O_2 sensor that regulates O_2supply in vivo.