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The Journal of Neuroscience, October 27, 2004, 24(43):9585-9597; doi:10.1523/JNEUROSCI.2569-04.2004

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Neurobiology of Disease
Na-K-Cl Cotransporter-Mediated Intracellular Na⁺ Accumulation Affects Ca²⁺ Signaling in Astrocytes in an In Vitro Ischemic Model

Brett Lenart,¹ Douglas B. Kintner,¹ Gary E. Shull,³ and Dandan Sun^1,2

Departments of ¹Neurosurgery and ²Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53792, and ³Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267

Na-K-Cl cotransporter isoform 1 (NKCC1) plays an important role in maintenance of intracellular Na⁺, K⁺, and Cl^- levels in astrocytes. We propose that NKCC1 may contribute to perturbations of ionic homeostasis in astrocytes under ischemic conditions. After 3-8 hr of oxygen and glucose deprivation (OGD), NKCC1-mediated ⁸⁶Rb influx was significantly increased in astrocytes from NKCC1 wild-type (NKCC1^+/+) and heterozygous mutant (NKCC1^+/-) mice. Phosphorylated NKCC1 protein was increased in NKCC1^+/+ astrocytes at 2 hr of OGD. Two hours of OGD and 1 hr of reoxygenation (OGD/REOX) triggered an 3.6-fold increase in intracellular Na⁺ concentration ([Na⁺]_i) in NKCC1^+/+ astrocytes. Inhibition of NKCC1 activity by bumetanide or ablation of the NKCC1 gene significantly attenuated the rise in [Na⁺]_i. Moreover, NKCC1^+/+ astrocytes swelled by 10-30% during 20-60 min of OGD. Either genetic ablation of NKCC1 or inhibition of NKCC1 by bumetanide-attenuated OGD-mediated swelling. An NKCC1-mediated increase in [Na⁺]_i may subsequently affect Ca²⁺ signaling through the Na⁺/Ca²⁺ exchanger (NCX). A rise in [Ca²⁺]_i was detected after OGD/REOX in the presence of a sarcoplasmic-endoplasmic reticulum (ER) Ca²⁺-ATPase inhibitor thapsigargin. Moreover, OGD/REOX led to a significant increase in Ca²⁺ release from ER Ca²⁺ stores. Furthermore, KB-R7943 (2-[2-[4(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate), an inhibitor of reverse-mode operation of NCX, abolished the OGD/REOX-induced enhancement in filling of ER Ca²⁺ stores. OGD/REOX-mediated Ca²⁺ accumulation in ER Ca²⁺ stores was absent when NKCC1 activity was ablated or pharmacologically inhibited. These findings imply that stimulation of NKCC1 activity leads to Na⁺ accumulation after OGD/REOX and that subsequent reverse-mode operation of NCX contributes to increased Ca²⁺ accumulation by intracellular Ca²⁺ stores.

Key words: cortical astrocytes; ischemia; intracellular Ca²⁺; astrocyte swelling; Na⁺ influx; Na⁺/Ca²⁺ exchange

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Received March 10, 2004; revised August 26, 2004; accepted August 28, 2004.

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