TY - JOUR

T1 - Molecular mechanisms of K+ clearance and extracellular space shrinkage—Glia cells as the stars

AU - MacAulay, Nanna

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - extracellular space shrinkage

KW - glia

KW - glia cell swelling

KW - K clearance

KW - Kir4.1

KW - Na/K-ATPase

KW - NKCC1

KW - spatial buffering

U2 - 10.1002/glia.23824

DO - 10.1002/glia.23824

M3 - Review

C2 - 32181522

AN - SCOPUS:85081721826

VL - 68

SP - 2192

EP - 2211

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 11

ER -