新型阳离子通道ANO8的电生理特性及其在神经病理性疼痛中的作用机制研究

Anoctamin(ANO)家族是一类具有8次跨膜结构的膜蛋白,包括ANO1-ANO10十个成员。各成员的特点和生理学功能差异很大,有些成员已被证实是离子通道。ANO8在基因进化角度上与其它成员差异最大，目前对其的功能特点、是否也是离子通道，鲜有报道。我们前期结果显示: ANO8为cAMP/PKA激活的阳离子通道；在DRG中主要表达在非肽能中小直径神经元；敲低DRG中 的ANO8缓解了小鼠的神经病理性疼痛；在神经病理性疼痛状态下，DRG中ANO8介导的阳离子内流功能性增强。本项目将采用电生理学、药理学、分子生物学、行为学等检测手段，研究 1）ANO8的电生理学特性；2）ANO8在神经病理性疼痛发生和维持中的作用；3）ANO8参与疼痛调节的机制。本研究将阐明ANO8作为cAMP激活的新型阳离子通道的电生理特性及其在神经病理性疼痛中的作用和机制，为研发以ANO8为靶点的镇痛药物提供思路。

The Anoctamin (ANO) protein family is a class of membrane proteins with 8 transmembrane domains, including ten members(ANO1-ANO10). The characteristics and physiological functions of each member are quite different. Some members have been proven to be ion channels. ANO8 is very different from other members in terms of genetic evolution, and its physiological characteristics function and whether it is ion channel have not been studied yet. Our preliminary data showed that:(1) ANO8 was a cation channel activated by cAMP/PKA; (2) ANO8 was mainly expressed in non-peptidergic small-medium diameter neurons in the DRG; (3) Knocking down ANO8 in the DRG alleviated hyperalgesia and allodynia in neuropathic pain mice.(4)The inward cationic current mediated by ANO8 in DRG was enhanced under neuropathic pain states. In this project, we will use electrophysiology, molecular biology, pharmacology, and animal behavior methods to investigate (1) The electrophysiological characteristics of ANO8; (2) The role of ANO8 in the development and maintenance of neuropathic pain; (3) The mechanism of ANO8 in neuropathic pain at the gene, ion channel, and cell level. This research will not only reveal the electrophysiological properties of ANO8 and its role and mechanism in neuropathic pain, but also provide ideas for the development of novel analgesic drugs.