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

<jats:title>Abstract</jats:title><jats:p>Neuronal signaling in the central nervous system (CNS) associates with release of K<jats:sup>+</jats:sup> into the extracellular space resulting in transient increases in [K<jats:sup>+</jats:sup>]<jats:sub>o</jats:sub>. This elevated K<jats:sup>+</jats:sup> is swiftly removed, in part, via uptake by neighboring glia cells. This process occurs in parallel to the [K<jats:sup>+</jats:sup>]<jats:sub>o</jats:sub> elevation and glia cells thus act as K<jats:sup>+</jats:sup> sinks during the neuronal activity, while releasing it at the termination of the pulse. The molecular transport mechanisms governing this glial K<jats:sup>+</jats:sup> absorption remain a point of debate. Passive distribution of K<jats:sup>+</jats:sup> via Kir4.1‐mediated spatial buffering of K<jats:sup>+</jats:sup> has become a favorite within the glial field, although evidence for a <jats:italic>quantitatively significant contribution</jats:italic> from this ion channel to K<jats:sup>+</jats:sup> clearance from the extracellular space is sparse. The Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>‐ATPase, but not the Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>/Cl<jats:sup>−</jats:sup> cotransporter, NKCC1, shapes the activity‐evoked K<jats:sup>+</jats:sup> transient. The different isoform combinations of the Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup>‐ATPase expressed in glia cells and neurons display different kinetic characteristics and are thereby distinctly geared toward their temporal and quantitative contribution to K<jats:sup>+</jats:sup> clearance. The glia cell swelling occurring with the K<jats:sup>+</jats:sup> transient was long assumed to be directly associated with K<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup>‐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<jats:sup>+</jats:sup> and extracellular space dynamics.</jats:p>