Astrocytic and neuronal accumulation of elevated extracellular K(+) with a 2/3 K(+)/Na(+) flux ratio-consequences for energy metabolism, osmolarity and higher brain function.

Brain excitation increases neuronal Na(+) concentration by 2 major mechanisms: (i) Na(+) influx caused by glutamatergic synaptic activity; and (ii) action-potential-mediated depolarization by Na(+) influx followed by repolarizating K(+) efflux, increasing extracellular K(+) concentration. This review deals mainly with the latter and it concludes that clearance of extracellular K(+) is initially mainly effectuated by Na(+),K(+)-ATPase-mediated K(+) uptake into astrocytes, at K(+) concentrations above ~10 mM aided by uptake of Na(+),K(+) and 2 Cl(-) by the cotransporter NKCC1. Since operation of the astrocytic Na(+),K(+)-ATPase requires K(+)-dependent glycogenolysis for stimulation of the intracellular ATPase site, it ceases after normalization of extracellular K(+) concentration. This allows K(+) release via the inward rectifying K(+) channel Kir4.1, perhaps after trans-astrocytic connexin- and/or pannexin-mediated K(+) transfer, which would be a key candidate for determination by synchronization-based computational analysis and may have signaling effects. Spatially dispersed K(+) release would have little effect on extracellular K(+) concentration and allow K(+) accumulation by the less powerful neuronal Na(+),K(+)-ATPase, which is not stimulated by increases in extracellular K(+). Since the Na(+),K(+)-ATPase exchanges 3 Na(+) with 2 K(+), it creates extracellular hypertonicity and cell shrinkage. Hypertonicity stimulates NKCC1, which, aided by β-adrenergic stimulation of the Na(+),K(+)-ATPase, causes regulatory volume increase, furosemide-inhibited undershoot in [K(+)]e and perhaps facilitation of the termination of slow neuronal hyperpolarization (sAHP), with behavioral consequences. The ion transport processes involved minimize ionic disequilibria caused by the asymmetric Na(+),K(+)-ATPase fluxes.