title: Role of the Astrocytic Na(+), K(+)-ATPase in K(+) Homeostasis in Brain: K(+) Uptake, Signaling Pathways and Substrate Utilization.
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 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.
authors.affiliation: 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.
authors.forename: Leif
authors.initials: L
authors.lastname: Hertz
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Junnan
authors.initials: J
authors.lastname: Xu
authors.affiliation: 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. lpeng@mail.cmu.edu.cn.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Gibbs
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology* / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D004734:Energy Metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D011188:Potassium / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium
keywords: Astrocytic Na+, K+-ATPase; Brain potassium homeostasis; Extracellular hypertonicity in brain; Glycogenolysis; Ouabain signaling; β1-Adrenergic signaling