Selective potentiation of 2-APB-induced activation of TRPV1-3 channels by acid.
Selective potentiation of 2-APB-induced activation of TRPV1-3 channels by acid.
复制标题
酸选择性增强 2-APB 诱导的 TRPV1-3 通道激活。
DOI：
10.1038/srep20791
复制
发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Yao J
中科院分区：
文献类型：
--
作者：
Gao L;Yang P;Qin P;Lu Y;Li X;Tian Q;Li Y;Xie C;Tian JB;Zhang C;Tian C;Zhu MX;Yao J
温度敏感的TRP通道对疼痛和炎症反应很重要，而组织酸中毒是这两种反应的主要因素。然而，除了TRPV1，其他ThermoTRP通道的酸感应仍然是一个谜。在TRPV1-3通道中，我们发现TRPV3通道是独一无二的，它可以被细胞质侧的质子直接激活。这种效应非常弱，涉及关键的细胞质残基L508、D512、S518或A520。然而，这些残基的突变并不影响TRPV1-3常见激动剂2-氨基乙氧基二苯硼酸盐（2-APB）引发的TRPV3电流的强质子诱导增强，无论配体是从细胞外还是细胞质侧施加。酸增强在TRPV1-3中很常见，仅在2- apb相关配体中可见。利用1h核磁共振检查2-APB及其类似物的溶液结构，我们观察到含硼化合物在中性/碱性与酸性pH下的显著结构差异，这表明基于2-APB的药物的pH依赖性配置开关可能是其功能的基础。为了支持这一观点，质子也增强了2-APB对TRPM8的抑制作用。总的来说，我们的研究结果揭示了2-APB对TRP通道作用的新见解，这将有助于设计针对这些通道的新药。
Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1–3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1–3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1–3 and only seen with 2-APB-related ligands. Using 1H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels.