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.

Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

“…Astrocytes maintain a low intracellular Na + concentration of 10–15 mM at rest, which is achieved by the action of the NKA, the only relevant export pathway for Na + across the plasma membrane [ 49 , 102 ]. Astrocytes predominately express α2/β2 subunits of the NKA, which exhibit a K D of ~4 mM for extracellular K + , making it ideally suited to take up K + released by active neurons [ 103 ]. NKA thus not only determines intracellular Na + and K + of astrocytes, but also contributes to regulation of extracellular K + .…”

“…Under physiological conditions, astrocytes take up K + released from active neurons by both channel- and transport-mediated mechanisms and thereby regulate neuronal excitability [ 37 , 82 , 103 , 146 ]. Exogenous application of glutamate, in contrast, resulted in a decline in astrocytic K + , most likely as a consequence of activation of EAATs [ 147 ].…”

On the origin of ultraslow spontaneous Na+ fluctuations in neurons of the neonatal forebrain

“…We observe that smaller neurons in general exhibit larger Na + fluctuations (p>0.001, Figure 5A, left panels). Both the amplitude and frequency of fluctuations decrease as we increase r in (Figure 5A The expression levels of astrocytic channels and transporters involved in K + uptake (Na + /K + ATPase, Kir4.1 channels, and Na + /K + /Clco-transporter 1 (NKCC1)) and connexins forming gap junctions are low in neonates [20,21]. Astrocytes in the neonate brain, therefore, have a lower capacity for uptake of extracellular K + released by neurons [19].…”

“…Notably, a range of factors that play a key role in controlling the dynamics of extra-and intracellular ion concentrations, are not fully developed in the neonate forebrain [13,[19][20][21][22]. These factors, such as the cellular uptake capacity of K + from the extracellular space (ECS), the expression levels of the three isoforms (a1, a2, and a3) of the Na + /K + pump that restore resting Na + and K + concentrations, the ratio of intra-to extracellular volumes, and the magnitude of relative shrinkage of the ECS in response to neuronal stimulus, all increase with age and cannot be easily manipulated experimentally [19].…”

Approaches to Study Gap Junctional Coupling

“…Gap junctional coupling is important for homeostasis of K + (Wallraff et al, 2006;Pannasch et al, 2011;Breithausen et al, 2020;MacAulay, 2020), Na + (Langer et al, 2012;Augustin et al, 2016;Moshrefi-Ravasdjani et al, 2017;Wadle et al, 2018), Cl − (Egawa et al, 2013), and neurotransmitters (Pannasch et al, 2011;Chaturvedi et al, 2014). Furthermore, regulated gap junctional coupling is mandatory for activity-dependent redistribution of metabolites, such as glucose (Cruz et al, 2007;Rouach et al, 2008;.…”