Molecular Basis of Somatic Sensation

描述(申请人提供)：温度敏感通道在高温或低温下打开，并调节我们对环境温度的感知。这些通道中的一些还调节非热诱导的痛觉。这些温敏通道由躯体感觉神经节细胞和皮肤细胞表达。我们已经发现了一种新的热门通道，它是通过从令人痛苦的低温变暖而激活的。这个通道是通过止痛而不是引起疼痛的热刺激来激活的。我们在皮肤细胞系中发现了这种热感电流。我们还发现，编码这一通道的基因由皮肤细胞表达，可能也表达于支配皮肤的体感神经节。我们建议通过膜片钳记录来确定什么温度变化打开和关闭这条通道，什么药物阻断或不能阻断它，以及什么离子通过它。我们打算通过原位杂交和抗体检测方法找出哪些细胞表达该通道的基因和蛋白，并将使用钙成像或电生理方法来确定这些细胞是否在功能上表达所产生的温度敏感通道。最后，我们将确定敲除Trpml3基因的效果，重点是细胞和整个动物对温度和其他感官刺激的生理反应。这些研究旨在阐明我们如何感知环境温度的变化，以及如何产生抗伤害或愉悦的感觉。与公共健康相关：目前已知的热敏通道项目并不能解释我们所感知的所有热刺激。此外，除了伤害性感受器的激活减少外，目前还没有关于如何检测到愉悦或缓解疼痛的刺激的知识。当从痛苦的寒冷中变暖时，温度变化激活了TRPML3通道，这可能有助于理解热感觉和疼痛缓解。

Description (provided by applicant): Thermosensitive channels open at hot or cold temperatures and mediate our perception of environmental temperature. Some of these channels also mediate non-thermally induced sensations of pain. These thermosensitive channels are expressed by cells of somatosensory ganglia as well as by cells of the skin. We have discovered a novel thermally gated channel activated by warming from painfully cold temperatures. This channel is activated by pain-relieving rather than pain-causing thermal stimulation. We find this thermally-induced current in a skin cell line. We also find that the gene encoding this channel is expressed by cells of the skin and perhaps also of the somatosensory ganglia that innervate the skin. We propose to determine by patch clamp recordings what temperature changes open and close this channel, what drugs block or fail to block it, and what ions pass through it. We intend to find out by in situ hybridization and antibody detection methods which cells express this channel's gene and protein, and will use calcium imaging or electrophysiological methods to determine whether these cells functionally express the resulting thermosensitive channel. Finally, we will determine the effects of knocking out the Trpml3 gene, focusing on the physiological response of cells and whole animals to temperature and other sensory stimuli. These studies aim to elucidate how we detect environmental temperature changes but also how antinociceptive or pleasurable sensation may take place. PUBLIC HEALTH RELEVANCE: Project Currently known thermosensitive channels do not account for all thermal stimuli we perceive. Furthermore, there is presently no knowledge of how pleasurable or pain- relieving stimuli may be detected other than by decreased activation of nociceptive receptors. The activation of TRPML3 channels by temperature changes when warming from painful cold may contribute to the understanding of both thermal sensation and pain relief.