GAPDH一种主要位于细胞浆中的糖酵解酶。然而，近期的研究表明GAPDH可被多种细胞分泌到细胞外，并参与神经细胞的神经突生成。另外还有报道称GAPDH可表达于巨噬细胞的表面，作为转铁蛋白的受体。然而，由于GAPDH是一个leaderless蛋白，它是如何到达细胞外环境的机制尚不明确。该研究小组检测了位于大脑的巨噬细胞-小神经胶质细胞的GAPDH的非传统释放中一种ATP门控阳离子通道-P2x7受体的作用。 ATP激活P2x7受体促进LPS预处理的小神经胶质细胞的GAPDH的释放。ATP诱导的microvesicle形成，exosome释放，和caspase-1激活导致的K+流出等与GAPDH释放有关，但是ATP诱导的膜孔通道的扩张、溶酶体胞吐作用与GAPDH释放无关。同时证明了外源性的GAPDH促进APS诱导小神经胶质细胞p38 MAP kinase的磷酸化。这些发现表明P2x7受体在小神经胶质细胞的GAPDH的非传统释放中起了重要作用，并且GAPDH释放到细胞外可能参与了大脑中的神经炎症反应的调节。
Takenouchi, T., et al. (2015). Extracellular ATP induces unconventional release of glyceraldehyde-3-phosphate dehydrogenase from microglial cells. Immunol Lett.2015 Oct;167(2):116-24.
Abstract: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that is predominantly localized in the cytoplasm. However, recent studies have suggested that GAPDH is released by various cells and that extracellular GAPDH is involved in the regulation of neuritogenesis in neuronal cells. It has also been reported that GAPDH is expressed on the surfaces of macrophages and functions as a transferrin receptor. However, since GAPDH is a leaderless protein the mechanisms by which it reaches the extracellular environment remain unclear. Here, we examined the role of P2x7 receptor (P2x7R), an ATP-gated cation channel, in the unconventional release of GAPDH from microglial cells, the resident macrophages in the brain. The activation of P2x7R by ATP triggered GAPDH release from lipopolysaccharide (LPS)-primed microglial cells. ATP-induced microvesicle formation, exosome release, and K+ efflux followed by caspase-1 activation are likely involved in the GAPDH release, but ATP-induced dilatation of membrane pores and lysosome exocytosis are not. It was also demonstrated that exogenous GAPDH facilitated LPS-induced phosphorylation of p38 MAP kinase in microglial cells. These findings suggest that P2x7R plays an important role in the unconventional release of GAPDH from microglial cells, and the GAPDH released into the extracellular space might be involved in the regulation of the neuroinflammatory response in the brain.
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