Molecular mechanisms of K+ clearance and extracellular space shrinkage—Glia cells as the stars

Abstract Neuronal signaling in the central nervous system (CNS) associates with release of K + into the extracellular space resulting in transient increases in [K + ] o . This elevated K + is swiftly removed, in part, via uptake by neighboring glia cells. This process occurs in parallel to the [K + ] o elevation and glia cells thus act as K + sinks during the neuronal activity, while releasing it at the termination of the pulse. The molecular transport mechanisms governing this glial K + absorption remain a point of debate. Passive distribution of K + via Kir4.1‐mediated spatial buffering of K + has become a favorite within the glial field, although evidence for a quantitatively significant contribution from this ion channel to K + clearance from the extracellular space is sparse. The Na + /K + ‐ATPase, but not the Na + /K + /Cl − cotransporter, NKCC1, shapes the activity‐evoked K + transient. The different isoform combinations of the Na + /K + ‐ATPase expressed in glia cells and neurons display different kinetic characteristics and are thereby distinctly geared toward their temporal and quantitative contribution to K + clearance. The glia cell swelling occurring with the K + transient was long assumed to be directly associated with K + uptake and/or AQP4, although accumulating evidence suggests that they are not. Rather, activation of bicarbonate‐ and lactate transporters appear to lead to glial cell swelling via the activity‐evoked alkaline transient, K + ‐mediated glial depolarization, and metabolic demand. This review covers evidence, or lack thereof, accumulated over the last half century on the molecular mechanisms supporting activity‐evoked K + and extracellular space dynamics.