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

摘要

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.