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

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 beta(1)-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 beta(1)-adrenergic signaling and inhibitable by its antagonists.