Glutamate transporter activity promotes enhanced Na+/K+-ATPase-mediated extracellular K+ management during neuronal activity

Abstract

Neuronal activity is associated with transient [K⁺]_o increases. The excess K⁺ is cleared by surrounding astrocytes, partly by the Na⁺/K⁺-ATPase of which several subunit isoform combinations exist. The astrocytic Na⁺/K⁺-ATPase α2β2 isoform constellation responds directly to increased [K⁺]_o but Na⁺/K⁺-ATPase-mediated K⁺ clearance could, in addition, be governed by astrocytic [Na⁺]_i. During most neuronal activity, glutamate is released in the synaptic cleft and is re-absorbed by astrocytic Na⁺-coupled glutamate transporters, thereby elevating [Na⁺]_i. It thus remains unresolved whether the different Na⁺/K⁺-ATPase isoforms are controlled by [K⁺]_o or [Na⁺]_i during neuronal activity. Hippocampal slice recordings of stimulus-induced [K⁺]_o transients with ion-sensitive microelectrodes revealed reduced Na⁺/K⁺-ATPase-mediated K⁺ management upon parallel inhibition of the glutamate transporter. The apparent intracellular Na⁺ affinity of isoform constellations involving the astrocytic β2 has remained elusive due to inherent expression of β1 in most cell systems as well as technical challenges in measuring intracellular affinity in intact cells. We therefore expressed the different astrocytic isoform constellations in Xenopus oocytes and determined their apparent Na⁺ affinity in intact oocytes and isolated membranes. The Na⁺/K⁺-ATPase was not fully saturated at basal astrocytic [Na⁺]_i, irrespective of isoform constellation, although the β1 subunit conferred lower apparent Na⁺ affinity to the α1 and α2 isoforms than the β2 isoform. In summary, enhanced astrocytic Na⁺/K⁺-ATPase-dependent K⁺ clearance was obtained with parallel glutamate transport activity. The astrocytic Na⁺/K⁺-ATPase isoform constellation α2β1 appeared specifically geared to respond to the [Na⁺]_i transients associated with activity-induced glutamate transporter activity.

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