Contributions of the Na + /K + ‐ATPase, NKCC1, and Kir4.1 to hippocampal K + clearance and volume responses
Open accessAbstract
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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Astrocytes play an important role in maintaining extracellular K+ homeostasis in the CNS, as well as H+, Cl-, and Ca2+ homeostasis.
“Astrocytes play an important role in maintaining extracellular K + homeostasis in the CNS, as well as H + , Cl - , and Ca 2+ homeostassis. 218”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [218]
The Introduction (page not provided) describes astrocytic uptake of extracellular K+, and the Results report mechanisms of K+ clearance. The paper does not establish the additional claim that astrocytes maintain extracellular H+, Cl−, and Ca2+ homeostasis; its mention of Cl− cotransport is not evidence for that broader claim. (LLM, conf=0.88)
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- Authors
- Larsen, B. R., Assentoft, M., Cotrina, M. L., Hua, S. Z., Nedergaard, M., Kaila, K., Voipio, J., & MacAulay, N.
- Affiliations
- University of Copenhagen (DK)
- University of Rochester Medicine (US)
- University at Buffalo, State University of New York (US)
- University of Helsinki (FI)
- Corresponding author
- MacAulay, Nanna
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2014-01-30
- Volume
- 62
- Issue
- 4
- Pages
- 608-622
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC4302754
- OpenAlex
- W1815876215
- Cited by
- 269
- References
- 57
- Citations by year
- 2026: 13 · 2025: 31 · 2024: 17 · 2023: 13 · 2022: 24 · 2021: 24 · 2020: 23 · 2019: 28 · 2018: 20 · 2017: 23 · 2016: 21 · 2015: 18 · 2014: 13 · 2013: 1
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeckfonden (R67-2010-6171, R44-2009-4181)
- National Institute on Aging (R01AG048769)
- National Institute of Neurological Disorders and Stroke (R01NS078304, R01NS078167, R01NS075177)
- National Institute of Dental and Craniofacial Research (R01DE022743)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD076892)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Na+/K+-ATPase, NKCC1, Kir4.1, potassium clearance, astrocytes, hippocampus, extracellular space volume, astrocyte swelling, neuronal network activity
- MeSH terms
- Kcnj10 Channel, Sodium-Potassium-Exchanging ATPase, Animals, Animals, Newborn, Bumetanide, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Hippocampus, Male, Membrane Potentials, Oocytes, Potassium, Xenopus laevis, Rats, Sprague-Dawley, Excitatory Amino Acid Agonists, Potassium Channels, Inwardly Rectifying, Extracellular Fluid, Sodium Potassium Chloride Symporter Inhibitors, Rats, Solute Carrier Family 12, Member 2, In Vitro Techniques
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