Role of STIM1 in Somatosensation

描述(由申请人提供)：环境温度变化可能是极端的。许多物种，包括哺乳动物，都是恒温的，为了有效的新陈代谢和生存，它们严格调节内部温度。为了调节温度的动态平衡，我们进化出了各种感知温度的机制。其中最具特点的或许是体感神经元的温度敏感性--这种神经元专门感知环境中温度的变化，反映在皮肤等外围组织中。瞬时受体电位(TRP)家族离子通道的一个子集被称为热TRPs，被证明是由不同的温度激活的，在躯体感觉神经元中表达，并且是外周温度感觉所必需的。有趣的是，在角质形成细胞中，至少有两个这样的热TRPs也表达，这意味着皮肤细胞参与了热感觉。许多温度色氨酸基因敲除的小鼠都有温度感觉缺陷。然而，我们实验室最近未发表的数据表明，热TRPs不太可能解释体感系统的所有温度感觉能力。皮肤细胞经历广泛的温度变化，除了可能参与热感觉外，还有助于炎症和热诱导的血管扩张。此外，其他组织/细胞热敏感性的分子机制目前尚不清楚。我们最近发现STIM1/Orai1离子通道复合体具有强烈的温度敏感性。这项提议将建立在这些初步数据的基础上，并追求这样一个普遍假设，即这些对温度敏感的离子通道在感知温度方面发挥着至关重要的作用。

DESCRIPTION (provided by applicant): Environmental temperature variations can be extreme. Many species, including mammals, are homeothermic, and tightly regulate internal temperatures for efficient metabolism and survival. To regulate temperature homeostasis, we have evolved various mechanisms to sense temperature. Perhaps best characterized among these is the thermosensitivity of somatosensory neurons - specialized to sense environmental changes in temperature as reflected in peripheral tissues such as the skin. A subset of Transient Receptor Potential (TRP) family of ion channels dubbed thermoTRPs are shown to be activated by distinct temperatures, are expressed in somatosensory neurons, and are required for peripheral thermosensation. Interestingly, at least two of these thermoTRPs are also expressed in keratinocytes, implicating skin cells in thermosensation. Many of the thermoTRP knockout mice have thermosensory deficits. However, recent unpublished data from our lab suggests that thermoTRPs are unlikely to explain all of the thermosensory capability of the somatosensory system. Skin cells experience wide temperature variations and contribute to inflammation and heat-induced vasodilation, in addition to potentially being involved in thermosensation. Furthermore, the molecular mechanism of thermosensitivity of other tissues/cells is not currently known. We have recently shown that STIM1/Orai1 ion channel complex is acutely thermosensitive. This proposal will build on these preliminary data and pursue the general hypothesis that these temperature- sensitive ion channels play an essential role in sensing temperature.