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Am J Physiol Cell Physiol 284: C475-C486, 2003. First published October 3, 2002; doi:10.1152/ajpcell.00383.2002
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Vol. 284, Issue 2, C475-C486, February 2003

Na+ pump alpha 2-subunit expression modulates Ca2+ signaling

Vera A. Golovina1, Hong Song1, Paul F. James2, Jerry B. Lingrel3, and Mordecai P. Blaustein1

1 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201; 2 Department of Zoology, Miami University, Oxford, Ohio 45056; and 3 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

The role of the Na+ pump alpha 2-subunit in Ca2+ signaling was examined in primary cultured astrocytes from wild-type (alpha 2+/+ = WT) mouse fetuses and those with a null mutation in one [alpha 2+/- = heterozygote (Het)] or both [alpha 2-/- = knockout (KO)] alpha 2 genes. Na+ pump catalytic (alpha ) subunit expression was measured by immunoblot; cytosol [Na+] ([Na+]cyt) and [Ca2+] ([Ca2+]cyt) were measured with sodium-binding benzofuran isophthalate and fura 2 by using digital imaging. Astrocytes express Na+ pumps with both alpha 1- (approx 80% of total alpha ) and alpha 2- (approx 20% of total alpha ) subunits. Het astrocytes express approx 50% of normal alpha 2; those from KO express none. Expression of alpha 1 is normal in both Het and KO cells. Resting [Na+]cyt = 6.5 mM in WT, 6.8 mM in Het (P > 0.05 vs. WT), and 8.0 mM in KO cells (P < 0.001); 500 nM ouabain (inhibits only alpha 2) equalized [Na+]cyt at 8 mM in all three cell types. Resting [Ca2+]cyt = 132 nM in WT, 162 nM in Het, and 196 nM in KO cells (both P < 0.001 vs. WT). Cyclopiazonic acid (CPA), which inhibits endoplasmic reticulum (ER) Ca2+ pumps and unloads the ER, induces transient (in Ca2+-free media) or sustained (in Ca2+-replete media) elevation of [Ca2+]cyt. These Ca2+ responses to 10 µM CPA were augmented in Het as well as KO cells. When CPA was applied in Ca2+-free media, the reintroduction of Ca2+ induced significantly larger transient rises in [Ca2+]cyt (due to Ca2+ entry through store-operated channels) in Het and KO cells than in WT cells. These results correlate with published evidence that alpha 2 Na+ pumps and Na+/Ca2+ exchangers are confined to plasma membrane microdomains that overlie the ER. The data suggest that selective reduction of alpha 2 Na+ pump activity can elevate local [Na+] and, via Na+/Ca2+ exchange, [Ca2+] in the tiny volume of cytosol between the plasma membrane and ER. This, in turn, augments adjacent ER Ca2+ stores and thereby amplifies Ca2+ signaling without elevating bulk [Na+]cyt.

astrocytes; catalytic subunit; fura 2; sodium-binding benzofuran isophthalate; sodium-potassium-adenosine 5'-triphosphatase isoforms; transgenic mice


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