Molecular mechanisms of K clearance and extracellular space shrinkage-Glia cells as the stars.

Neuronal signaling in the central nervous system (CNS) associates with release of K into the extracellular space resulting in transient increases in [K ] . This elevated K is swiftly removed, in part, via uptake by neighboring glia cells. This process occurs in parallel to the [K ] 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.