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神经元通过钠-钾泵(Na+,K+-AT-Pase)在细胞浆中富集钾离子并排出细胞内的钠离子,从而维持细胞膜内外的钠和钾离子浓度梯度,调控细胞膜电位和兴奋性,该过程对调节神经元功能起到十分重要的作用。但是,人们一直不清楚除了ATP、钠和钾离子对钠-钾泵的驱动作用以及一些神经递质、激素通过它们的受体间接地调节钠-钾泵活性以外,身体内是否存在可以直接激动钠-钾泵的物质,并对神经系统功能进行调节。我们的研究发现传导痛觉的背根节神经元高表达滤泡素抑制素样蛋白1(follistatin-like1,FSTL1),并通过清亮小泡将FSTL1运输至脊髓内的传入神经终末释放,直接与位于感觉传入神经终末突触前膜上的钠-钾泵α1亚基相结合,增强钠-钾泵活性,使细胞膜超极化,从而对感觉传入神经终末的兴奋性突触传递起抑制性调控作用。我们与南京大学模式动物研究所高翔研究组密切合作,制备了国内第一例条件式敲除小鼠,在背根节神经元中特异性敲除了FSTL1的基因。研究发现FSTL1条件式敲除小鼠兴奋性突触传递增强,痛觉敏感度提高。因此,FSTL1作为第一个被发现的内源性钠-钾泵激动剂,对于保持正常的躯体感觉是必需的,FSTL1减少则会导致异常痛觉。该发现表明内源性钠-钾泵激动剂可以通过调控突触传递对神经系统功能产生重要的影响。
Neurons accumulate potassium ions in the cytoplasm through the sodium-potassium pump (Na +, K + -AT-Pase) and excrete intracellular sodium ions, thereby maintaining the gradient of sodium and potassium ion concentration inside and outside the cell membrane, regulating the membrane potential and excitability , The process plays a very important role in regulating neuronal function. However, it remains unclear whether there is a direct excitement in the body other than the driving effect of ATP, sodium and potassium on the sodium-potassium pump and some neurotransmitters, which indirectly regulate sodium-potassium pump activity through their receptors Sodium-potassium pump substance, and regulate nervous system function. Our study found that dorsal root ganglion neurons that induce pain hyperesthesia express follistatin-like 1 (FSTL1) and are delivered directly to the afferent nerve terminals that transport FSTL1 to the spinal cord via clear vesicles, directly Binds to the sodium-potassium pump [alpha] 1 subunit located on the presynaptic membrane that senses afferent nerve terminals, enhances sodium-potassium pump activity, hyperpolarizes the cell membrane, and thereby excites excitatory synapses that sense afferent terminals Transmission from the regulatory role of inhibition. We worked closely with the Gao Xiang research group at Model Animal Research Institute of Nanjing University to prepare the first conditional knockout mouse in our country and specifically knock out the FSTL1 gene in dorsal root ganglion neurons. The study found that FSTL1 conditional knockout mice increased excitatory synaptic transmission, increased pain sensitivity. Thus, FSTL1, the first discovered endogenous sodium-potassium pump agonist, is essential for maintaining normal somatosensory conditions and a reduction in FSTL1 results in abnormal allodynia. This finding suggests that endogenous sodium-potassium pump agonists may have important effects on nervous system function by regulating synaptic transmission.