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

Research output: Contribution to journalReviewResearchpeer-review

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.

Original languageEnglish
Issue number11
Pages (from-to)2192-2211
Number of pages20
Publication statusPublished - 2020

    Research areas

  • extracellular space shrinkage, glia, glia cell swelling, K clearance, Kir4.1, Na/K-ATPase, NKCC1, spatial buffering

ID: 245370284