2023-08-31 バッファロー大学(UB)
The complex biological phenomena that allows us to feel heat and pain is being unraveled by researchers in the Jacobs School of Medicine and Biomedical Sciences at UB.
◆この研究は、副作用が少ない新しい鎮痛剤の設計に向けた第一歩となり、温度感知受容体が高いエネルギーを必要とするため、通常の構造変化では不可能なエネルギー供給手段として自己破壊的なプロセスを使用することが示唆されています。これにより、新しい治療法の開発に道を開く可能性があります。
<関連情報>
- https://www.buffalo.edu/news/releases/2023/08/Heat-and-pain-detection-enabled-by-ion-channel-mechanism.html
- https://www.pnas.org/doi/10.1073/pnas.2300305120
TRPV1の絶妙な温度感受性の自己破壊メカニズム A suicidal mechanism for the exquisite temperature sensitivity of TRPV1
Andrew Mugo, Ryan Chou, Felix Chin, Beiying Liu, Qiu-Xing Jiang, and Feng Qin
Proceedings of the National Academy of Sciences Published:August 28, 2023
DOI:https://doi.org/10.1073/pnas.2300305120
Significance
The vanilloid receptor TRPV1 is a prototype temperature receptor for detecting noxious heat among other pain-producing signals at peripheral nerve endings. Its strong temperature sensitivity requires a large energetic change in channel opening. But the underlying mechanism has not been elucidated. Here, we directly measured the heat uptake of TRPV1 by differential scanning calorimetry on reconstituted channels in vesicles. We show that the thermal transition in TRPV1 is accompanied with energetic changes on a scale sufficient to compromise protein stability. Our findings suggest that coupling functional activation to irreversible conformation transitions is important for TRPV1 to attain its exquisite temperature sensitivity, which, from a thermodynamic stand, may be a common mechanism for strongly temperature-dependent biological processes.
Abstract
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.
