TRP-like channel ANKTM1 in vivo

描述（由申请人提供）：已证明几个TRP通道可通过热刺激直接门控。TRPV 1是第一个被鉴定的温度激活的TRP，对有害热（42 ℃）和辣椒素有反应，并且在背根神经节（DRG）的伤害感受（疼痛感测）神经元亚群中特异性表达。TRPM 8在DRG中的一个单独的神经元群体中表达，对低温（25 ℃）和薄荷醇有反应。它们不同的感觉方式和表达模式表明TRPV 1和TRPM 8通过不同的途径传递“热”和“冷”信号。最近，我发现了ANKTM 1，这是一种对有害的低温（17 ℃）有反应的TRP样通道，在一个也表达TRPV 1的伤害感受神经元亚群中表达。我还发现培养的DRG神经元对有害的热和冷都有反应，但对薄荷醇没有反应，这表明传递凉爽/愉快信号的神经元与传递有害的热和冷的神经元是分开的。因此，我建议TRPV 1和ANKTM 1一起标记“多模态伤害感受器”，即传递几种疼痛模式的神经元。这个提议的中心假设是，感觉神经元中的ANKTM 1激活在体内激发疼痛信号。这一假设是基于初步数据，水杨酸甲酯，ANKTM 1的特异性激活剂，导致小鼠的伤害性行为。这项提议的主要目的是通过使用水杨酸甲酯作为感官读数来检查ANKTM 1激活的后果。该提案的目的是将RNAi应用于培养的神经元和小鼠的行为测定和基因敲除。这些研究将进一步阐明ANKTM 1在温度和疼痛检测中的作用。

DESCRIPTION (provided by applicant): Several TRP channels have been shown to be directly gated by thermal stimuli. TRPV1, the first temperature-activated TRP identified, responds to noxious heat (42C) and to capsaicin and is specifically expressed in a subset of nociceptive (pain sensing) neurons in the dorsal root ganglia (DRG). TRPM8, expressed in a separate population of neurons in the DRG, responds to cool temperatures (25C) and to menthol. Their distinct sensory modalities and expression patterns suggest that TRPV1 and TRPM8 transmit "hot" and "cool" signals via different pathways. Recently I identified ANKTM1, a TRP-like channel that responds to noxious cold temperatures (17C) and is expressed in a subset of nociceptive neurons that also express TRPV1. I also identified DRG neurons in culture that respond to both noxious heat and cold, but not to menthol, suggesting neurons that transmit a cool/pleasant signal are separate from those that convey both noxious heat and cold. I therefore propose that together TRPV1 and ANKTM1 mark "polymodal nociceptors," neurons that transmit several painful modalities. The central hypothesis of this proposal is that ANKTM1 activation in sensory neurons elicits a painful signal in vivo. This hypothesis is based on preliminary data that Methyl Salicylate, a specific activator of ANKTM1, causes nociceptive behaviors in mice. The broad objective of this proposal is to examine the consequences of ANKTM1 activation by using Methyl Salicylate as a sensory readout. The aims of the proposal apply RNAi in cultured neurons and behavioral assays and gene knockout in mice. These studies will further elucidate the role of ANKTM1 in temperature and pain detection.