Contributions of the Na+/K+‐ATPase,NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses |
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Authors: | Brian Roland Larsen Mette Assentoft Maria L Cotrina Susan Z Hua Maiken Nedergaard Kai Kaila Juha Voipio Nanna MacAulay |
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Institution: | 1. Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;2. School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York;3. Department of Mechanical and Aerospace Engineering, University of Buffalo, Buffalo, New York;4. Department of Biosciences, University of Helsinki, Helsinki, Finland;5. Neuroscience Center, University of Helsinki, Helsinki, Finland |
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Abstract: | Network activity in the brain is associated with a transient increase in extracellular K+ concentration. The excess K+ is removed from the extracellular space by mechanisms proposed to involve Kir4.1‐mediated spatial buffering, the Na+/K+/2Cl? cotransporter 1 (NKCC1), and/or Na+/K+‐ATPase activity. Their individual contribution to K+]o management has been of extended controversy. This study aimed, by several complementary approaches, to delineate the transport characteristics of Kir4.1, NKCC1, and Na+/K+‐ATPase and to resolve their involvement in clearance of extracellular K+ transients. Primary cultures of rat astrocytes displayed robust NKCC1 activity with K+]o increases above basal levels. Increased K+]o produced NKCC1‐mediated swelling of cultured astrocytes and NKCC1 could thereby potentially act as a mechanism of K+ clearance while concomitantly mediate the associated shrinkage of the extracellular space. In rat hippocampal slices, inhibition of NKCC1 failed to affect the rate of K+ removal from the extracellular space while Kir4.1 enacted its spatial buffering only during a local K+]o increase. In contrast, inhibition of the different isoforms of Na+/K+‐ATPase reduced post‐stimulus clearance of K+ transients. The astrocyte‐characteristic α2β2 subunit composition of Na+/K+‐ATPase, when expressed in Xenopus oocytes, displayed a K+ affinity and voltage‐sensitivity that would render this subunit composition specifically geared for controlling K+]o during neuronal activity. In rat hippocampal slices, simultaneous measurements of the extracellular space volume revealed that neither Kir4.1, NKCC1, nor Na+/K+‐ATPase accounted for the stimulus‐induced shrinkage of the extracellular space. Thus, NKCC1 plays no role in activity‐induced extracellular K+ recovery in native hippocampal tissue while Kir4.1 and Na+/K+‐ATPase serve temporally distinct roles. GLIA 2014;62:608–622 |
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Keywords: | extracellular ion homeostasis cell volume changes in mammalian brain ion transport |
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