Molecular Basis of Somatic Sensation

描述（由申请人提供）：热敏通道在高温或低温下打开，调节我们对环境温度的感知。其中一些通道也介导非热诱导的疼痛感觉。这些热敏通道由体感神经节细胞和皮肤细胞表达。我们发现了一种新的热门控通道，通过极度寒冷的温度升温来激活。这个通道是由缓解疼痛而不是引起疼痛的热刺激激活的。我们在皮肤细胞系中发现了这种热感应电流。我们还发现，编码这个通道的基因是由皮肤细胞表达的，也许也包括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个通道，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了该通道的基因和蛋白质，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了由此产生的热敏通道。最后，我们将确定敲除Trpml3基因的效果，重点关注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检测环境温度的变化，以及如何产生抗感觉或愉悦的感觉。公共卫生相关性：项目目前已知的热敏通道并不能解释我们感知到的所有热刺激。此外，除了伤害感受器的激活减少之外，目前还不知道如何检测到愉悦或缓解疼痛的刺激。当疼痛性寒冷变暖时，温度变化对TRPML3通道的激活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.