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 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.