Requirement of Glycogenolysis for Uptake of Increased Extracellular K+ in Astrocytes: Potential Implications for K+ Homeostasis and Glycogen Usage in Brain

The importance of astrocytic K+ uptake for extracellular K+ ([K+]e) clearance during neuronal stimulation or pathophysiological conditions is increasingly acknowledged. It occurs by preferential stimulation of the astrocytic Na+,K+-ATPase, which has higher Km and Vmax values than its neuronal counterpart, at more highly increased [K+]e with additional support of the cotransporter NKCC1. Triggered by a recent DiNuzzo et al. paper, we used administration of the glycogenolysis inhibitor DAB to primary cultures of mouse astrocytes to determine whether K+ uptake required K+-stimulated glycogenolysis. KCl was increased by either 5 mM (stimulating only the Na+,K+-ATPase) or 10 mM (stimulating both transporters) in glucose-containing saline media prepared to become iso-osmotic after the addition. DAB completely inhibited both uptakes, the Na+,K+-ATPase-mediated by preventing Na+ uptake for stimulation of its intracellular Na+-activated site, and the NKCC1-mediated uptake by inhibition of depolarization- and L-channel-mediated Ca2+ uptake. Drugs inhibiting the signaling pathways involved in either of these processes also abolished K+ uptake. Assuming similar in vivo characteristics, partly supported by literature data, K+-stimulated astrocytic K+ uptake must discontinue after normalization of extracellular K+. This will allow Kir1.4-mediated release and reuptake by the less powerful neuronal Na+,K+-ATPase.