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Articles in PresS, published online ahead of print December 19, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00538.2001
Submitted on November 9, 2001
Accepted on December 13, 2001
1 Neurosurgery, University of Wisconsin Medical School, Madison, WI, USA; Physiology, University of Wisconsin Medical School, Madison, WI, USA
2 Neurosurgery, University of Wisconsin Medical School, Madison, WI, USA
3 Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: sun{at}neurosurg.wisc.edu.
We reported previously that inhibition of the Na+-K+-Cl- cotransporter (NKCC) by bumetanide abolishes high [K+]o-induced swelling and intracellular Cl- accumulation in rat cortical astrocytes. In this report, we extended our study using cortical astrocytes from NKCC1-deficient (NKCC1-/-) mice. The NKCC1 protein was absent in NKCC1-/- astrocytes, revealed by immunoblotting and immunofluorescence staining. The basal level of NKCC1 activity was 21.9 ± 4.9 nmol/mg/min in wild-type (NKCC1+/+) astrocytes, but was essentially absent (4.2 ± 3.8 nmol/mg/min) in NKCC1-/- astrocytes. 75 mM [K+]o increased NKCC1 activity ~ 4-fold increase in NKCC1+/+ cells (p<0.05), but had no effect in NKCC1-/- astrocytes. As NKCC1+/+ astrocytes were exposed to 75 mM [K+]o for 4 min, intracellular Cl- was increased by 70% (p<0.05). In contrast, intracellular Cl- remained unchanged in NKCC1-/- astrocytes. Baseline [Na+]i in NKCC1+/+ astrocytes was 19.0 ± 0.5 mM, as compared to 16.9 ± 0.3 mM [Na+]i in NKCC1-/- astrocytes (p<0.05). A significant decrease in [Na+]i was found in NKCC1+/+ and NKCC1-/- astrocytes under 75 mM [K+]o. Relative cell volume of NKCC1+/+ astrocytes increased by 13 ± 2% in 75 mM [K+]o, compared to a value of 1.0 ± 0.5% in NKCC1-/- astrocytes (p<0.05). Regulatory volume increase (RVI) following hypertonic shrinkage was completely impaired in NKCC1-/- astrocytes. High [K+]o-induced [14C]-D-aspartate release was reduced by ~30% in NKCC1-/- astrocytes. Taken together, our study suggests that stimulation of NKCC1 is required for high [K+]o-induced swelling, which contributes to glutamate release from astrocytes in high [K+]o.
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