QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Lenart, B. Articles by Sun, D. Search for Related Content PubMed PubMed Citation Articles by Lenart, B. Articles by Sun, D.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				L. Smith, N. Smallwood, A. Altman, and C. M. Liedtke PKC{delta} Acts Upstream of SPAK in the Activation of NKCC1 by Hyperosmotic Stress in Human Airway Epithelial Cells J. Biol. Chem., August 8, 2008; 283(32): 22147 - 22156. [Abstract] [Full Text] [PDF]

				H. D. Bauser-Heaton, J. Song, and H. G. Bohlen Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2166 - H2173. [Abstract] [Full Text] [PDF]

				D. B. Kintner, J. Luo, J. Gerdts, A. J. Ballard, G. E. Shull, and D. Sun Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1113 - C1122. [Abstract] [Full Text] [PDF]

				S. F. Pedersen, M. E. O'Donnell, S. E. Anderson, and P. M. Cala Physiology and pathophysiology of Na+/H+ exchange and Na+-K+-2Cl- cotransport in the heart, brain, and blood Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R1 - R25. [Abstract] [Full Text] [PDF]

				J. R. Paulson, K. E. Roder, G. McAfee, D. D. Allen, C. J. Van der Schyf, and T. J. Abbruscato Tobacco Smoke Chemicals Attenuate Brain-to-Blood Potassium Transport Mediated by the Na,K,2Cl-Cotransporter during Hypoxia-Reoxygenation J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 248 - 254. [Abstract] [Full Text] [PDF]

				J. Luo, H. Chen, D. B. Kintner, G. E. Shull, and D. Sun Decreased Neuronal Death in Na+/H+ Exchanger Isoform 1-Null Mice after In Vitro and In Vivo Ischemia J. Neurosci., December 7, 2005; 25(49): 11256 - 11268. [Abstract] [Full Text] [PDF]

				D. B. Kintner, A. Look, G. E. Shull, and D. Sun Stimulation of astrocyte Na+/H+ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2 Am J Physiol Cell Physiol, October 1, 2005; 289(4): C934 - C945. [Abstract] [Full Text] [PDF]

				C. Sheldon, A. Diarra, Y. M. Cheng, and J. Church Sodium Influx Pathways during and after Anoxia in Rat Hippocampal Neurons J. Neurosci., December 8, 2004; 24(49): 11057 - 11069. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help