A suicidal mechanism for the exquisite temperature sensitivity of TRPV1.
A suicidal mechanism for the exquisite temperature sensitivity of TRPV1.
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TRPV1 精致的温度敏感性的自杀机制。
DOI：
10.1073/pnas.2300305120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Qin,Feng
中科院分区：
文献类型：
--
作者：
Mugo,Andrew;Chou,Ryan;Chin,Felix;Liu,Beiying;Jiang,Qiu-Xing;Qin,Feng
香草酸受体 TRPV1 是一种精致的有害热伤害感受器，但其温度传感机制尚未明确。热力学表明该通道必须经历异常高能的变构转变。因此，直接测量这种转变的能量对于正确破译其温度传感机制至关重要。此前，利用亚毫秒温度跃变和膜片钳记录，我们估计 TRPV1 打开的热激活会引起 100 kcal/mol 量级的焓变。尽管这种能量的规模是其他已知生物受体无法比拟的，但蛋白质中通常不完美的变构耦合意味着驱动 TRPV1 转变的实际热量吸收量可能要大得多。在本文中，我们应用差示扫描量热法直接监测 TRPV1 中伴随温度诱导构象转变的热流。我们的测量表明，热量会在 TRPV1 中引发强大、复杂的热转变，包括通道开放和部分蛋白质展开转变，并且这两个过程本质上是耦合的。我们的研究结果支持不可逆蛋白质解折叠（通常被认为对生理功能具有破坏性）对于 TRPV1 热转导至关重要，并且可能对生物学中其他强烈依赖温度的过程至关重要。
The vanilloid receptor TRPV1 is an exquisite nociceptive sensor of noxious heat, but its temperature-sensing mechanism is yet to define. Thermodynamics dictate that this channel must undergo an unusually energetic allosteric transition. Thus, it is of fundamental importance to measure directly the energetics of this transition in order to properly decipher its temperature-sensing mechanism. Previously, using submillisecond temperature jumps and patch-clamp recording, we estimated that the heat activation for TRPV1 opening incurs an enthalpy change on the order of 100 kcal/mol. Although this energy is on a scale unparalleled by other known biological receptors, the generally imperfect allosteric coupling in proteins implies that the actual amount of heat uptake driving the TRPV1 transition could be much larger. In this paper, we apply differential scanning calorimetry to directly monitor the heat flow in TRPV1 that accompanies its temperature-induced conformational transition. Our measurements show that heat invokes robust, complex thermal transitions in TRPV1 that include both channel opening and a partial protein unfolding transition and that these two processes are inherently coupled. Our findings support that irreversible protein unfolding, which is generally thought to be destructive to physiological function, is essential to TRPV1 thermal transduction and, possibly, to other strongly temperature-dependent processes in biology.