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

74 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
Pages (from-to)480-486
Number of pages7
JournalCardiovascular Research
Volume95
Issue number4
DOIs
StatePublished - Sep 1 2012

Bibliographical note

Funding Information:
This work was partially supported by the American Heart Association (0735084N to S.D.) and the National Institutes of Health (HL109501 to S.D., HL81526 to D.M.B., HL28573 to J.L.).

Funding

This work was partially supported by the American Heart Association (0735084N to S.D.) and the National Institutes of Health (HL109501 to S.D., HL81526 to D.M.B., HL28573 to J.L.).

FundersFunder number
National Institutes of Health (NIH)HL81526, HL28573
National Heart, Lung, and Blood Institute (NHLBI)R01HL109501
American Heart Association0735084N

    Keywords

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

    ASJC Scopus subject areas

    • General Medicine

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