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cotransporter-null mice exhibit absence of swelling and decrease in
EAA release
Departments of 1 Neurosurgery and 2 Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53792; and 3 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267
We reported previously that inhibition of
Na+-K+-Cl
cotransporter isoform 1 (NKCC1) by bumetanide abolishes high extracellular K+
concentration ([K+]o)-induced swelling and
intracellular Cl accumulation in rat cortical astrocytes.
In this report, we extended our study by using cortical astrocytes from
NKCC1-deficient (NKCC1/) mice. NKCC1 protein and
activity were absent in NKCC1/ astrocytes.
[K+]o of 75 mM increased NKCC1 activity
approximately fourfold in NKCC1+/+ cells (P < 0.05) but had no effect in NKCC1/ astrocytes.
Intracellular Cl was increased by 70% in
NKCC1+/+ astrocytes under 75 mM
[K+]o (P < 0.05) but
remained unchanged in NKCC1/ astrocytes. Baseline
intracellular Na+ concentration
([Na+]i) in NKCC1+/+ astrocytes
was 19.0 ± 0.5 mM, compared with 16.9 ± 0.3 mM
[Na+]i in NKCC1/ astrocytes
(P < 0.05). Relative cell volume of
NKCC1+/+ astrocytes increased by 13 ± 2% in 75 mM
[K+]o, compared with a value of 1.0 ± 0.5% in NKCC1/ astrocytes (P < 0.05).
Regulatory volume increase after hypertonic shrinkage was completely
impaired in NKCC1/ astrocytes.
High-[K+]o-induced 14C-labeled
D-aspartate release was reduced by ~30% in
NKCC1/ astrocytes. Our study suggests that stimulation
of NKCC1 is required for high-[K+]o-induced
swelling, which contributes to glutamate release from astrocytes under
high [K+]o.
cell swelling; high potassium ion concentration; cultured astrocytes; glutamate release; bumetanide; intracellular chloride; excitatory amino acid
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