Na+/K+-ATPase α2-isoform preferentially modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ release in cardiac myocytes

Sanda Despa, Jerry B. Lingrel, Donald M Bers

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Aims Na+/K+-ATPase (NKA) is essential in regulating [Na+]i, and thus cardiac myocyte Ca2+ and contractility via Na+/Ca2+ exchange. Different NKA-α subunit isoforms are present in the heart and may differ functionally, depending on specific membrane localization. In smooth muscle and astrocytes, NKA-α2 is located at the junctions with the endo(sarco)plasmic reticulum, where they could regulate local [Na+], and indirectly junctional cleft [Ca 2+]. Whether this model holds for cardiac myocytes is unclear. Methods and resultsThe ouabain-resistant NKA-α1 cannot be selectively blocked to assess its effect. To overcome this, we used mice in which NKA-α1 is ouabain sensitive and NKA-α2 is ouabain resistant (SWAP mice). We measured the effect of ouabain at low concentration on [Na +]i, Ca2+ transients, and the fractional sarcoplasmic reticulum (SR) Ca2+ release in cardiac myocytes from wild-type (WT; NKA-α2 inhibition) and SWAP mice (selective NKA-α1 block). At baseline, Na+ and Ca2+ regulations are similar in WT and SWAP mice. For equal levels of total NKA inhibition (∼25%), ouabain significantly increased Ca2+ transients (from ΔF/F0 1.5 ± 0.1 to 1.8 ± 0.1), and fractional SR Ca2+ release (from 24 ± 3 to 29 ± 3) in WT (NKA-α2 block) but not in SWAP myocytes (NKA-α1 block). This occurred despite a similar and modest increase in [Na+]i (∼2 mM) in both groups. The effect in WT mice was mediated specifically by NKA-α2 inhibition because at a similar concentration ouabain had no effect in transgenic mice where both NKA-α1 and NKA-α2 are ouabain resistant. ConclusionNKA-α2 has a more prominent role (vs. NKA-α1) in modulating cardiac myocyte SR Ca 2+ release.

Original languageEnglish (US)
Pages (from-to)480-486
Number of pages7
JournalCardiovascular Research
Volume95
Issue number4
DOIs
StatePublished - Sep 1 2012

Keywords

  • Na /Ca exchanger
  • Na/K-ATPase
  • Ouabain
  • SarcolemmaSR junctions

ASJC Scopus subject areas

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

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