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Am J Physiol Cell Physiol (October 3, 2002). doi:10.1152/ajpcell.00383.2002
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Articles in PresS, published online ahead of print October 2, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00383.2002
Submitted on August 26, 2002
Accepted on September 30, 2002

Na+ Pump Alpha-2 Subunit Expression Modulates Ca2+ Signaling

Vera A Golovina1*, Hong Song1, Paul F James2, Jerry B Lingrel1, and Mordecai P Blaustein3

1 Physiology, U. of Maryland Med. Sch., Baltimore, Maryland, USA
2 Zoology, Miami University, Oxford, Ohio, USA
3 Molec. Genetics, Biochem., U. Cincinnati Coll. Med., Cincinnati, Ohio, USA

* To whom correspondence should be addressed. E-mail: vgolovin{at}umaryland.edu.

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+/- =Het) or both ({alpha}2-/- =KO) {alpha}2 genes. Na+ pump catalytic (a) subunit expression was measured by immunoblot; cytosol Na+ and Ca2+ concentrations ([Na+]CYT and [Ca2+]CYT) were measured with SBFI and Fura-2 using digital imaging. Astrocytes express Na+ pumps with both a1 (about 80% of total {alpha}) and {alpha}2 (about 20% of total a) subunits. Het astrocytes express about 50% of normal {alpha}2; those from KO express none. Expression of a1 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 mM 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 (PM) 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 PM and ER. This, in turn, augments adjacent ER Ca2+ stores and thereby amplifies Ca2+ signaling without elevating bulk [Na+]CYT.




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