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Role of the Astrocytic Na+, K+-ATPase in K+ Homeostasis in Brain: K+ Uptake, Signaling Pathways and Substrate Utilization

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Abstract

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 Ca2+ decrease. A requirement of Na+, K+-ATPase signaling for extracellular Ca2+ makes K+ uptake (and brain edema) selectively dependent upon β1-adrenergic signaling and inhibitable by its antagonists.

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Acknowledgments

The study was supported by Grants No. 31440048 from the National Natural Science Foundation of China to LP.

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  1. 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

    Leif Hertz, Dan Song, Junnan Xu & Liang Peng

  2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia

    Marie E. Gibbs

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  1. Leif Hertz
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  2. Dan Song
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Correspondence to Liang Peng.

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Special Issue: In Honor of Dr. Gerald Dienel.

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Hertz, L., Song, D., Xu, J. et al. Role of the Astrocytic Na+, K+-ATPase in K+ Homeostasis in Brain: K+ Uptake, Signaling Pathways and Substrate Utilization. Neurochem Res 40, 2505–2516 (2015). https://doi.org/10.1007/s11064-014-1505-x

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