伤害性感受器TRPV2通道功能多样，在机体的热痛感觉、化学刺激和机械刺激感觉等过程中发挥重要作用，但由于TRPV2极高的温度激活阈值（>52℃），加之目前缺乏专一的工具药物或调节亚基，而使得对TRPV2通道门控和调节机制的研究相对滞后。而我们在前期预实验中发现了多种内源性因素均可以有效调节TRPV2通道功能，包括：1）生理浓度范围的Ca2+和Mg2+均能显著地增强TRPV2的活性，而Ba2+和Zn2+则对TRPV2起抑制作用；2）TRPV2兼具Ca2+依赖和Ca2+不依赖两种脱敏特性；3）通过酵母双杂交实验筛选得到多个与TRPV2互作的候选蛋白，初步结果显示其中的KCNAB1亚基通过与TRPV2互作而提高TRPV2通道的上膜量。基于前期发现，本研究旨在阐明上述内源性调节因素对TRPV2通道功能的调节机理，所获研究结果将有助于丰富内源性调控TRPV2活性的手段，促进TRPV2的生理功能研究。

Nociceptive receptor TRPV2 channel is one member of the transient receptor potential (TRP) superfamily, sharing the common property of polymodal gating as many other TRP channels. An increasing number of studies have suggested that TRPV2 channels are involved in diverse cellular processes and play important roles in thermal pain sensation, chemosensation and mechanical sensation. To date, the researches on TRPV2 are slower than other TRP channels because of its reported activation by extremely high temperatures (>52℃), and as well as the scarcity of specific endogenous ligands or regulatory subunits and/or pharmacological drugs. In our preliminary experiments, we interestingly found that: 1) Ca2+ at physiological concentrations would not only cause the desensitization of TRPV2 channels, but also increase the sensitivities of TRPV2 to its agonist and thus enhance the channel activities. Moreover, our results revealed that TRPV2 also has a calcium-independent desensitization in addition to calcium-dependent desensitization; 2) Mg2+ within the physiological concentrations also remarkably enhanced TRPV2 channel functions, while Ba2+ and Zn2+ could respectively inhibit TRPV2 channel currents; 3) Through yeast two-hybrid experiments, we found several potential regulatory and accessory proteins interacting with TRPV2 channels in native tissues. One of them, KCNAB1 has been shown to interact with TRPV2 by our coimmunoprecipitation (CO-IP) analysis, and we further found that co-expression with KCNAB1 would increase cell surface expression levels of TRPV2. Based upon our preliminary data, this proposed research therefore aims to elucidate the effects and the mechanisms underlying upregulation of TRPV2 channel functions by Ca2+ and Mg2+ at physiological concentrations, respectively. Also, we will compare and demonstrate the differences between Ca2+-dependent and Ca2+-independent desensitization, and find out how to recover TRPV2 function from the desensitized state. In addition to clarify the protein-protein interaction of TRPV2 with potential interaction partners discovered in our previous yeast two-hybrid experiments, we will demonstrate how KCNAB1 interacts with TRPV2 channel protein and the mechanism underlying KCNAB1 increased cell surface expression levels of TRPV2 as well. Taken together, our research aims to define pathways that control and regulate the activities of TRPV2 channels. TRPV2 channel has been implicated in diverse physiological and pathophysiological processes, including thermo sensation, pain transduction, innate immunity and cancer. Therefore the proposed research will provide insightful information on regulating TRPV2 by endogenous factors and is critically important for a better understanding TRPV2 physiology.