Clearance of store-released Ca2+ by the Na+-Ca 2+ exchanger is diminished in aortic smooth muscle from Na +-K+-ATPase α2-isoform gene-ablated mice

Ronald M. Lynch, Craig S. Weber, Kevin D. Nullmeyer, Edwin D.W. Moore, Richard J. Paul

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Two α-isoforms of the Na+-K+-ATPase are expressed in vascular smooth muscle cells (VSMCs). The α1- isoform is proposed to serve a cytosolic housekeeping role, whereas the α2-isoform modulates Ca2+ storage via coupling to the Na+-Ca2+ exchanger (NCX) in a subsarcolemmal compartment. To evaluate the ramifications of this proposed interaction, Ca 2+-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 α2-isoform gene-ablated, homozygous null knockout (α2-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 α2-KO VSMCs, preferential clearance of store-released Ca2+ by NCX was lost, whereas PMCA activity was increased. Selective inhibition of the α2-isoform (0.5 μM ouabain for 20 min), before treatment with CPA enhanced the store load in VSMCs from WT, but not α2- KO mice. A subsequent analysis of capacitative Ca2+ entry (CCE) indicated that the magnitude of Ca2+ influx was significantly greater in α2-KO cells. Our findings support the concept of a subsarcolemmal space where the α2-isoform coupled with NCX modulates Ca2+-store function and, thereby, CCE.

Original languageEnglish (US)
Pages (from-to)H1407-H1416
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
StatePublished - Mar 2008


  • Calcium homeostasis
  • Calcium stores
  • Capacitative calcium influx
  • Plasma membrane calcium ATPase
  • Sarco(endo)plasmic reticulum calcium ATPase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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