内源性钠-钾泵激动剂调节痛觉信息传递

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一钾泵活性以外，身体内是否存在可以直接激动钠一钾泵的物质，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．1ike 1，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一钾泵仪1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一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。

Regulation of Nociceptive Transmission by Endogenous Activator of Na+-K+ Pump

Na+-K+ pump plays a crucial role in maintaining the Na+ and K+ gradient across the plasma membrane. This gradient is essential for maintaining the resting membrane potential and excitable properties of neurons. Na+-K+ pump activity is regulated by direct modulators (ATP, Na+, K+ and cardiotonic steroid inhibitor ouabain and digoxin) and indirect modulators (catecholamines, insulin, angiotensin II and morphine) through receptor-mediated mechanisms. However, it is unclear whether Na+-K+ pump could be regulated by any agonists expressed in neurons or other cells in the bodies. we found that Follistatin-Like 1 (FSTL1) was highly expressed in small-diameter neurons of the dorsal root ganglion (DRG). FSTL1 was transported to the afferent terminals via small translucent vesicles and secre-ted in both spontaneous and depolarization-induced manners. Interestingly, FSTL1 was found to bind the α1 subunit of Na+-K+ pump and elevate the pump activity. Extracellular FSTL1 induced membrane hyperpolarization in cultured cells and inhibited afferent synaptic transmission in spinal cord slices by activating Na+-K+ pump. In close collaboration with Dr. Xiang Gao’s laboratory at Nanjing university,they made genetic deletion of FSTL1 in small DRG neurons of mice. These mutant mice displayed enhancement of afferent synaptic transmission and sensory hypersensitivity. Thus, FSTL1-dependent activation of Na+-K+ pump regulates the threshold of somatic sensation, suggesting that the function of nervous system could be modulated by the endogenous Na+-K+ pump activator which regulates the synaptic transmission.