☆ 4.6 Article

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

JOURNAL OF PHYSIOLOGY-LONDON (2016)

Journal

JOURNAL OF PHYSIOLOGY-LONDON

Volume 594, Issue 22, Pages 6627-6641

Publisher

WILEY

DOI: 10.1113/JP272531

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Funding

Lundbeck Foundation
Danish Medical Research Council
Novo Nordisk Foundation
Riisfort Foundation
Lundbeck Foundation [R151-2013-14120, R48-2009-4638, R118-2012-11726] Funding Source: researchfish
Novo Nordisk Fonden [NNF14OC0013409] Funding Source: researchfish

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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 alpha 2 beta 2 isoform constellation responds directly to increased [K+] o but, in addition, Na+/K+-ATPase-mediated K+ clearance could 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 beta 2 has remained elusive as a result of inherent expression of beta 1 in most cell systems, as well as technical challenges involved 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 beta 1 subunit conferred lower apparent Na+ affinity to the alpha 1 and alpha 2 isoforms than the beta 2 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 alpha 2 beta 1 appeared to be specifically geared to respond to the [Na+](i) transients associated with activity-induced glutamate transporter activity.

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An interaction between PRRT2 and Na+/K+ ATPase contributes to the control of neuronal excitability

Bruno Sterlini, Alessandra Romei, Chiara Parodi, Davide Aprile, Michele Oneto, Anita Aperia, Pierluigi Valente, Flavia Valtorta, Anna Fassio, Pietro Baldelli, Fabio Benfenati, Anna Corradi

Summary: This study reveals that PRRT2 deficiency affects the function of Na+/K+ ATPase (NKA) in neurons, leading to increased clustering of NKA on the plasma membrane, which can be reversed by re-expression of PRRT2. Additionally, PRRT2 deficiency also reduces the NKA-dependent afterhyperpolarization in neurons following high-frequency firing.

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