A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8
A paradigm of thermal adaptation in penguins and elephants by tuning cold activation in TRPM8
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通过调节 TRPM8 中的冷激活来实现企鹅和大象热适应的范例
DOI：
10.1073/pnas.1922714117
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Lai Ren
中科院分区：
文献类型：
--
作者：
Yang Shilong;Lu Xiancui;Wang Yunfei;Xu Lizhen;Chen Xiaoying;Yang Fan;Lai Ren
意义感知温度对所有生物的生存至关重要。在这里，我们证明了在典型的温度敏感的TRPM8离子通道的冷诱导激活过程中，在暴露状态下稳定的孔域中存在疏水残基。调节这些残基的疏水性专门改变TRPM8中的冷反应。此外，脊椎动物中的TRPM8同源基因进化成使用这样一种机制，从生理上调节耐冷性以获得更好的热适应。我们的发现不仅促进了对TRPM8冷诱导激活机制的理解，也为脊椎动物环境适应的分子进化策略提供了启示。为了适应栖息地的温度，脊椎动物通过进化形成了复杂的生理和生态机制。瞬时受体电位Melastatin 8(TRPM8)是寒冷的主要感受器。然而，寒冷如何激活TRPM8，以及这种传感器如何调整以适应热适应，在很大程度上仍不清楚。在这里，我们通过膜片钳记录、非天然氨基酸成像和结构建模的组合，建立了TRPM8感受寒冷的分子框架。我们首次观察到TRPM8在八种不同脊椎动物(即非洲象和帝企鹅)中的最大冷激活时间是根据它们的栖息地温度进行调整的，这些脊椎动物在孔区(PD)具有不同的侧链疏水性(SCH)。我们进一步证明，随着溶剂可及性的变化，改变PD中残基的SCH会导致TRPM8中冷反应的特定调节。我们还观察到，表达企鹅TRPM8的敲门小鼠表现出显著的耐寒能力。综上所述，我们的发现提出了一种脊椎动物热适应的范例，其中TRPM8离子通道中冷激活的进化调节通过改变其PD中的SCH和溶剂可及性在很大程度上有助于冷敏感/耐受表型的设定。
Significance Sensing temperature is critical for the survival of all living beings. Here, we show that during cold-induced activation of the archetypical temperature-sensitive TRPM8 ion channel, there are hydrophobic residues in the pore domain stabilized in the exposed state. Tuning hydrophobicity of these residues specifically alters cold response in TRPM8. Furthermore, TRPM8 orthologs in vertebrates evolved to employ such a mechanism, which physiologically tunes cold tolerance for better thermal adaptation. Our findings not only advance the understanding of the cold-induced activation mechanism of TRPM8 but also bring insights to the molecular evolution strategy for ambient-temperature adaptation in vertebrates. To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular framework of how cold is sensed in TRPM8 with a combination of patch-clamp recording, unnatural amino acid imaging, and structural modeling. We first observed that the maximum cold activation of TRPM8 in eight different vertebrates (i.e., African elephant and emperor penguin) with distinct side-chain hydrophobicity (SCH) in the pore domain (PD) is tuned to match their habitat temperature. We further showed that altering SCH for residues in the PD with solvent-accessibility changes leads to specific tuning of the cold response in TRPM8. We also observed that knockin mice expressing the penguin’s TRPM8 exhibited remarkable tolerance to cold. Together, our findings suggest a paradigm of thermal adaptation in vertebrates, where the evolutionary tuning of the cold activation in the TRPM8 ion channel through altering SCH and solvent accessibility in its PD largely contributes to the setting of the cold-sensitive/tolerant phenotype.