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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1407    most recent 00855.2007v1 Alert me when this article is cited 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 Google Scholar Google Scholar Articles by Lynch, R. M. Articles by Paul, R. J. Search for Related Content PubMed PubMed Citation Articles by Lynch, R. M. Articles by Paul, R. J.

Clearance of store-released Ca²⁺ by the Na⁺-Ca²⁺ exchanger is diminished in aortic smooth muscle from Na⁺-K⁺-ATPase ₂-isoform gene-ablated mice

¹Departments of Physiology and Pharmacology, University of Arizona, Tucson, Arizona; ²Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and ³Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio

Submitted 23 July 2007 ; accepted in final form 8 January 2008

Two -isoforms of the Na⁺-K⁺-ATPase are expressed in vascular smooth muscle cells (VSMCs). The ₁-isoform is proposed to serve a cytosolic housekeeping role, whereas the ₂-isoform modulates Ca²⁺ storage via coupling to the Na⁺-Ca²⁺ exchanger (NCX) in a subsarcolemmal compartment. To evaluate the ramifications of this proposed interaction, Ca²⁺-store load and the contributions of the primary Ca²⁺ transporters to Ca²⁺ clearance were studied in aortic VSMCs from embryonic wild-type (WT) and Na⁺-K⁺-ATPase ₂-isoform gene-ablated, homozygous null knockout (₂-KO) mice. Ca²⁺ stores were unloaded by inhibiting the sarco(endo)plasmic reticulum Ca²⁺-ATPase with cyclopiazonic acid (CPA) in Ca²⁺-free media to limit Ca²⁺ influx. Ca²⁺ clearance by the plasma membrane Ca²⁺-ATPase (PMCA), NCX, or mitochondria was selectively inhibited. In WT VSMCs, NCX accounted for 90% of the Ca²⁺ efflux. In ₂-KO VSMCs, preferential clearance of store-released Ca²⁺ by NCX was lost, whereas PMCA activity was increased. Selective inhibition of the ₂-isoform (0.5 µM ouabain for 20 min), before treatment with CPA enhanced the store load in VSMCs from WT, but not ₂-KO mice. A subsequent analysis of capacitative Ca²⁺ entry (CCE) indicated that the magnitude of Ca²⁺ influx was significantly greater in ₂-KO cells. Our findings support the concept of a subsarcolemmal space where the ₂-isoform coupled with NCX modulates Ca²⁺-store function and, thereby, CCE.

calcium stores; calcium homeostasis; plasma membrane calcium ATPase; sarco(endo)plasmic reticulum calcium ATPase; capacitative calcium influx

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