温度敏感离子通道,例如存在于所有动物细胞中的TRP家族(thermo-TRP),用来感知热和冷的感觉。已经报道了相当多的蛋白质结构用于这些离子通道,为揭示它们的结构-功能关系提供了坚实的基础。先前的功能研究表明,TRP通道的热敏能力主要取决于其胞质结构域的特性。尽管它们在感知方面很重要,并且在开发合适的疗法方面有广泛的兴趣,急性和急剧温度介导的通道门控的确切机制仍然是神秘的。这里,我们提出了一个模型,其中热TRP通道通过亚稳态细胞质结构域的形成和解离直接感知外部温度。在平衡热力学的框架内描述了一个开-关双稳态系统,定义了类似于电压选通通道的V1/2参数的中点温度T1/2。基于通道开启概率与温度的关系,我们估计了典型热敏通道在构象变化过程中熵和焓的变化。我们的模型能够在实验确定的热通道开口曲线中准确地再现陡峭的活化阶段,因此应该极大地促进未来的实验验证。
Temperature-sensitive ion channels, such as those from the TRP family (thermo-TRPs) present in all animal cells, serve to perceive heat and cold sensations. A considerable number of protein structures have been reported for these ion channels, providing a solid basis for revealing their structure-function relationship. Previous functional studies suggest that the thermosensing ability of TRP channels is primarily determined by the properties of their cytosolic domain. Despite their importance in sensing and wide interests in the development of suitable therapeutics, the precise mechanisms underlying acute and steep temperature-mediated channel gating remain enigmatic. Here, we propose a model in which the thermo-TRP channels directly sense external temperature through the formation and dissociation of metastable cytoplasmic domains. An open-close bistable system is described in the framework of equilibrium thermodynamics, and the middle-point temperature T½ similar to the V½ parameter for a voltage-gating channel is defined. Based on the relationship between channel opening probability and temperature, we estimate the change in entropy and enthalpy during the conformational change for a typical thermosensitive channel. Our model is able to accurately reproduce the steep activation phase in experimentally determined thermal-channel opening curves, and thus should greatly facilitate future experimental verification.