Hertz Leif, Song Dan, Xu Junnan, Peng Liang, Gibbs Marie E
Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, No. 77 Puhe Road, Shenbei District, Shenyang, 110122, People's Republic of China.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia.
Neurochem Res. 2015 Dec;40(12):2505-16. doi: 10.1007/s11064-014-1505-x. Epub 2015 Jan 3.
This paper describes the roles of the astrocytic Na(+), K(+)-ATPase for K(+) homeostasis in brain. After neuronal excitation it alone mediates initial cellular re-accumulation of moderately increased extracellular K(+). At higher K(+) concentrations it is assisted by the Na(+), K(+), 2Cl(-) transporter NKCC1, which is Na(+), K(+)-ATPase-dependent, since it is driven by Na(+), K(+)-ATPase-created ion gradients. Besides stimulation by high K(+), NKCC1 is activated by extracellular hypertonicity. Intense excitation is followed by extracellular K(+) undershoot which is decreased by furosemide, an NKCC1 inhibitor. The powerful astrocytic Na(+), K(+)-ATPase accumulates excess extracellular K(+), since it is stimulated by above-normal extracellular K(+) concentrations. Subsequently K(+) is released via Kir4.1 channels (with no concomitant Na(+) transport) for re-uptake by the neuronal Na(+), K(+)-ATPase which is in-sensitive to increased extracellular K(+), but stimulated by intracellular Na(+) increase. Operation of the astrocytic Na(+), K(+)-ATPase depends upon Na(+), K(+)-ATPase/ouabain-mediated signaling and K(+)-stimulated glycogenolysis, needed in these non-excitable cells for passive uptake of extracellular Na(+), co-stimulating the intracellular Na(+)-sensitive site. A gradual, spatially dispersed release of astrocytically accumulated K(+) will therefore not re-activate the astrocytic Na(+), K(+)-ATPase. The extracellular K(+) undershoot is probably due to extracellular hypertonicity, created by a 3:2 ratio between Na(+), K(+)-ATPase-mediated Na(+) efflux and K(+) influx and subsequent NKCC1-mediated volume regulation. The astrocytic Na(+), K(+)-ATPase is also stimulated by β1-adrenergic signaling, which further stimulates hypertonicity-activation of NKCC1. Brain ischemia leads to massive extracellular K(+) increase and Ca(2+) decrease. A requirement of Na(+), K(+)-ATPase signaling for extracellular Ca(2+) makes K(+) uptake (and brain edema) selectively dependent upon β1-adrenergic signaling and inhibitable by its antagonists.
本文描述了星形胶质细胞钠钾ATP酶在脑内钾离子稳态中的作用。神经元兴奋后，它独自介导细胞外适度增加的钾离子的初始细胞再积累。在较高钾离子浓度下，它由钠钾2氯转运体NKCC1辅助，NKCC1依赖于钠钾ATP酶，因为它由钠钾ATP酶产生的离子梯度驱动。除了受高钾离子刺激外，NKCC1还受细胞外高渗激活。强烈兴奋后会出现细胞外钾离子过低，呋塞米（一种NKCC1抑制剂）可降低这种情况。强大的星形胶质细胞钠钾ATP酶积累过量的细胞外钾离子，因为它受高于正常的细胞外钾离子浓度刺激。随后，钾离子通过Kir4.1通道释放（无伴随的钠离子转运），以供神经元钠钾ATP酶重新摄取，神经元钠钾ATP酶对细胞外钾离子增加不敏感，但受细胞内钠离子增加刺激。星形胶质细胞钠钾ATP酶的运作依赖于钠钾ATP酶/哇巴因介导的信号传导和钾离子刺激的糖原分解，在这些非兴奋性细胞中，这是被动摄取细胞外钠离子所必需的，共同刺激细胞内钠离子敏感位点。因此，星形胶质细胞积累的钾离子的逐渐、空间分散释放不会重新激活星形胶质细胞钠钾ATP酶。细胞外钾离子过低可能是由于钠钾ATP酶介导的钠离子外流与钾离子内流之间3:2的比例以及随后NKCC1介导的体积调节所产生的细胞外高渗。星形胶质细胞钠钾ATP酶也受β1 - 肾上腺素能信号传导刺激，这进一步刺激NKCC1的高渗激活。脑缺血导致大量细胞外钾离子增加和钙离子减少。细胞外钙离子对钠钾ATP酶信号传导的需求使得钾离子摄取（以及脑水肿）选择性地依赖于β1 - 肾上腺素能信号传导，并可被其拮抗剂抑制。
