A specialized pore turret in the mammalian cation channel TRPV1 is responsible for distinct and species-specific heat activation thresholds
A specialized pore turret in the mammalian cation channel TRPV1 is responsible for distinct and species-specific heat activation thresholds
复制标题
哺乳动物阳离子通道 TRPV1 中的特殊孔塔负责不同且物种特异性的热激活阈值
DOI：
10.1074/jbc.ra120.013037
复制
发表时间：
2020-07-10
影响因子：
4.8
通讯作者：
Yang, Shilong
中科院分区：
文献类型：
--
作者：
Du, Guangxu;Tian, Yuhua;Yang, Shilong
瞬时受体电位香草酸1（TRPV1）通道是一种热激活的阳离子通道，在环境温度检测和热稳态中起着至关重要的作用。虽然TRPV1的几个结构特征已被证明参与热诱导激活的门控过程中，只有少数这些关键元素的生理意义已在进化的背景下进行了评估。在这里，使用HEK293细胞中的瞬时表达，电生理记录和分子建模，我们表明孔转塔包含结构和功能决定因素，这些决定因素设置了体温波动很大的哺乳动物中不同TRPV1直系同源物的热激活阈值。我们发现，TRPV1从蝙蝠短尾果蝇表现出较低的阈值温度的通道激活比它的人类直系同源物和三个蝙蝠特异性的氨基酸取代位于孔塔是足以确定这个阈值温度。此外，TRPV1孔转塔的结构似乎是区分物种特异性TRPV1直系同源物之间的热激活阈值的生理和进化意义。这些发现支持TRPV1孔转塔在调节热激活阈值方面的作用，并且它们表明其进化是通过适应暴露于可变温度的哺乳动物中的特定生理特征而驱动的。
The transient receptor potential vanilloid 1 (TRPV1) channel is a heat-activated cation channel that plays a crucial role in ambient temperature detection and thermal homeostasis. Although several structural features of TRPV1 have been shown to be involved in heat-induced activation of the gating process, the physiological significance of only a few of these key elements has been evaluated in an evolutionary context. Here, using transient expression in HEK293 cells, electrophysiological recordings, and molecular modeling, we show that the pore turret contains both structural and functional determinants that set the heat activation thresholds of distinct TRPV1 orthologs in mammals whose body temperatures fluctuate widely. We found that TRPV1 from the bat Carollia brevicauda exhibits a lower threshold temperature of channel activation than does its human ortholog and three bat-specific amino acid substitutions located in the pore turret are sufficient to determine this threshold temperature. Furthermore, the structure of the TRPV1 pore turret appears to be of physiological and evolutionary significance for differentiating the heat-activated threshold among species-specific TRPV1 orthologs. These findings support a role for the TRPV1 pore turret in tuning the heat-activated threshold, and they suggest that its evolution was driven by adaption to specific physiological traits among mammals exposed to variable temperatures.