Recovery from tachyphylaxis of TRPV1 coincides with recycling to the surface membrane
Recovery from tachyphylaxis of TRPV1 coincides with recycling to the surface membrane
复制标题
TRPV1 从快速耐受中恢复与再循环到表面膜同时发生
DOI：
10.1073/pnas.1819635116
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发表时间：
2019-03-12
影响因子：
11.1
通讯作者：
Yao, Jing
中科院分区：
文献类型：
--
作者：
Tian, Quan;Hu, Juan;Yao, Jing
瞬时受体电位香草酸亚型1（TRPV1）离子通道对于感知热痛和化学性疼痛至关重要。TRPV1激活伴随着钙离子依赖性脱敏；急性脱敏反映了刺激过程中通道活性的快速降低，而快速耐受则指TRPV1对重复刺激的反应减弱。急性脱敏被认为是TRPV1通道构象变化所致；然而，快速耐受形成的潜在机制仍有待明确。在此，我们报告全细胞TRPV1快速耐受的程度受诱导刺激强度的调控。我们利用光片显微镜和对pH敏感的pHluorin传感器来追踪TRPV1的胞吞和胞吐运输，从而获得实时信息，即不同程度的快速耐受与TRPV1按比例循环至质膜的过程同时发生。这一过程控制着TRPV1在细胞表面的表达水平，进而影响全细胞的伤害性感受反应。我们进一步表明，活性门控的TRPV1运输与具有不同动力学特征的细胞内钙离子信号相关，并且分别募集由突触结合蛋白1和7介导的循环途径。这些结果表明，依赖活性的TRPV1循环有助于快速耐受的形成。
Significance TRPV1 ion channel plays an important role in the transmission and modulation of pain. Desensitization of TRPV1 in nociceptors is adaptable for analgesic therapy. One type of desensitization is tachyphylaxis that reflects reduced TRPV1 responses to repetitive stimuli. To understand the mechanism underlying the whole-cell tachyphylaxis, here we used an orthogonal electro-optical approach integrating electrophysiology and light-sheet microscopy. We show that the intensity of tachyphylaxis is regulated by the strength of inducing stimulation, and that TRPV1 channels undergo activity-gated recycling to regulate their surface expression level thereby the degree of tachyphylaxis. This study provides real-time insights into the establishment of tachyphylaxis and helps to understand desensitization-based analgesics. The transient receptor potential vanilloid-1 (TRPV1) ion channel is essential for sensation of thermal and chemical pain. TRPV1 activation is accompanied by Ca2+-dependent desensitization; acute desensitization reflects rapid reduction in channel activity during stimulation, whereas tachyphylaxis denotes the diminution in TRPV1 responses to repetitive stimulation. Acute desensitization has been attributed to conformational changes of the TRPV1 channel; however, the mechanisms underlying the establishment of tachyphylaxis remain to be defined. Here, we report that the degree of whole-cell TRPV1 tachyphylaxis is regulated by the strength of inducing stimulation. Using light-sheet microscopy and pH-sensitive sensor pHluorin to follow TRPV1 endocytosis and exocytosis trafficking, we provide real-time information that tachyphylaxis of different degrees concurs with TRPV1 recycling to the plasma membrane in a proportional manner. This process controls TRPV1 surface expression level thereby the whole-cell nociceptive response. We further show that activity-gated TRPV1 trafficking associates with intracellular Ca2+ signals of distinct kinetics, and recruits recycling routes mediated by synaptotagmin 1 and 7, respectively. These results suggest that activity-dependent TRPV1 recycling contributes to the establishment of tachyphylaxis.