Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, China.
College of Food Science and Technology, Hainan University, 58 Renmin Avenue, Haikou, China.
Nat Commun. 2021 Mar 3;12(1):1401. doi: 10.1038/s41467-021-21731-1.
Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.
目前缺乏针对热敏感患者的有效治疗方法，这主要是因为我们对这种疾病的发病机制了解有限。在神经系统中，激活转录因子 4（ATF4）参与调节突触可塑性和记忆形成。在这里，我们表明 ATF4 在热伤害感受中发挥重要作用。事实上，敲除小鼠背根神经节（DRG）神经元中的 ATF4 会选择性地损害热敏感性。从机制上讲，我们表明 ATF4 与瞬时受体电位阳离子通道亚家族 M 成员 3（TRPM3）相互作用，并介导 DRG 神经元中 TRPM3 的膜转运以响应热。ATF4 的缺失也显著降低了 TRPM3 的电流和 KIF17 介导的转运，表明 KIF17/ATF4/TRPM3 复合物是神经元对热刺激反应所必需的。我们的研究结果揭示了 ATF4 在 DRG 神经元对热刺激反应中的非转录作用。
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