STIM1在温度感受中的作用

Thermosensation is crucial for maintaining body temperature homeostasis. It is generally believed that thermosensation is directly initiated by activation of temperature sensors located in free nerve endings of somatosensory neurons.To date, some members of temperature activated Transient Receptor Potential (TRP) channels, dubbed thermoTRPs,have been demonstrated to function as in vivo temperature sensors. However, a growing body of evidence suggest that other sensors must exist. STIM1/Orai1 constitutes the calcium release activated calcium (CRAC) channel that is critical for a variety of cellular functions such as gene expression. Interestingly, we have recently identified STIM1/Orai1 as a novel class of temperature activated ion channels, but its physiological significance needs to be addressed. Here we present unpublished data that STIM1 mediates a robust heat response in keratinocytes, and more importantly, that mice with STIM1 deficiency specifically in keratinocytes but not in somatosensory neurons display altered thermotaxis behaviors compared to control mice. Building on these preliminary data, we will employ STIM1 conditional knockout mice to comprehensively assay the in vivo role of STIM1 in keratinocytes in thermal preference assays, heat-induced nociception and hyperalgesia, and begin to explore the molecular mechanisms underlying STIM1-mediated temperature sensation .These studies will lead us to identify STIM1 as a novel in vivo temperature sensor, and propose that thermosensation can also be initiated by keratinocytes beside somatosensory neurons.

温度觉对维持机体体温平衡至关重要。目前普遍认为温度感受始发于温度直接激活位于初级感觉神经元神经末梢的温度受体。 一些thermoTRPs通道已被证实可以作为在体温度受体；但是有证据显示还存在别的温度受体。我们最近报导了STIM1/Orai1可以作为一类新型温度激活离子通道，但是其生理学意义有待阐明。该申请项目预实验结果显示STIM1能介导皮肤细胞的温度反应；皮肤细胞而非神经细胞特异性的STIM1基因敲除小鼠与对照组小鼠有不一样的温热感受。我们将利用细胞特异性的STIM1基因敲除小鼠来系统的研究表达在皮肤细胞中的STIM1在温热感受、热痛感受、热痛过敏中的作用，并初步探讨STIM1介导的温度感受的分子机制。本项目的研究有望首次证实：1）STIM1是一类新的在体温度受体；2）温度感受不一定如普遍认为的只能始发于初级感觉神经末梢，皮肤细胞也可以直感受外周温度变化而触发温度感受。

温度觉对维持机体体温平衡至关重要。目前普遍认为温度感受始发于温度直接激活位于初级感觉神经元神经末梢的温度受体。 一些thermoTRPs通道已被证实可以作为在体温度受体；但是有证据显示还存在别的温度受体。我们之前报导了内质网钙库浓度感受蛋白STIM1 可以作为一类新型温度激活分子，但是其温度敏感性的生理学意义有待阐明。基于前期研究结果显示STIM1在皮肤角质细胞中有高表达，而在初级感觉神经细胞中的表达微弱，因此在本项目中我们聚焦于探究表达在皮肤角质细胞而不是初级感觉神经元中的STIM1在躯体温度感受中的生理作用。我们构建了皮肤角质细胞特异性STIM1敲除小鼠（STIM1Ker/Ker KO）及STIM1温度敏感性缺失的STIM1-ΔK基因敲入小鼠。通过对原代培养的WT, STIM1Ker/Ker KO及STIM1-ΔK皮肤角质细胞进行单细胞钙成像检测，我们发现STIM1的温度敏感性介导皮肤细胞加热时（heat-on ）及降温过程中（heat-off ）出现的钙变化。通过对 WT, STIM1Ker/Ker KO及STIM1-ΔK小鼠进行一系列的行为学检测，我们发现STIM1Ker/Ker KO及STIM1-ΔK小鼠出现了类似的对温热选择的缺陷，而它们的其它行为学包括热痛、冷痛、触碰、运动及平衡能力都表现正常。这些研究结果不仅揭示了表达在皮肤细胞中的STIM1可以作为一类在体温度感受分子，其温度敏感性特异性的介导温热感受，也表明皮肤细胞可以触发温度感受。我们的研究结果为深入理解哺乳动物精细的温度感受机制提供了重要线索。