Roles of astrocytic Na+,K+-ATPase and glycogenolysis for K+ homeostasis in mammalian brain

Neuronal excitation increases extracellular K+ concentration ([K+](o)) in vivo and in incubated brain tissue by stimulation of postsynaptic glutamatergic receptors and by channel-mediated K+ release during action potentials. Convincing evidence exists that subsequent cellular K+ reuptake occurs by active transport, normally mediated by Na+,K+-ATPase. This enzyme is expressed both in neurons and in astrocytes but is stimulated by elevated [K+](o) only in astrocytes. This might lead to an initial K+ uptake in astrocytes, followed by Kir4.1-mediated release and neuronal reuptake. In cell culture experiments, K+-stimulated glycogenolysis is essential for operation of the astrocytic Na+,K+-ATPase resulting from the requirement for glycogenolysis in a pathway leading to uptake of Na+ for costimulation of its intracellular sodium-binding site. The astrocytic but not the neuronal Na+,K+-ATPase is additionally stimulated by isoproterenol, a -adrenergic agonist, but only at nonelevated [K+](o). This effect is also glycogenolysis dependent and might play a role during poststimulatory undershoots. Attempts to replicate dependence on glycogenolysis for K+ reuptake in glutamate-stimulated brain slices showed similar [K+](o) recovery half-lives in the absence and presence of the glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol. The undershoot was decreased, but to the same extent as an unexpected reduction of peak [K+](o) increase. A potential explanation for this difference from the cell culture experiments is that astrocytic glutamate uptake might supply the cells with sufficient Na+. Inhibition of action potential generation by tetrodotoxin caused only a marginal, nonsignificant decrease in stimulated [K+](o) in brain slices, hindering the evaluation if K+ reaccumulation after action potential propagation requires glycogenolysis in this preparation. (c) 2014 W iley Periodicals, Inc.