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 K m and V max 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 Ca 2+ 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.