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Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes.
- Source :
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Cardiovascular research [Cardiovasc Res] 2012 Sep 01; Vol. 95 (4), pp. 480-6. Date of Electronic Publication: 2012 Jun 27. - Publication Year :
- 2012
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Abstract
- Aims: Na(+)/K(+)-ATPase (NKA) is essential in regulating [Na(+)](i), and thus cardiac myocyte Ca(2+) and contractility via Na(+)/Ca(2+) 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.<br />Methods and Results: The 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), Ca(2+) transients, and the fractional sarcoplasmic reticulum (SR) Ca(2+) release in cardiac myocytes from wild-type (WT; NKA-α2 inhibition) and SWAP mice (selective NKA-α1 block). At baseline, Na(+) and Ca(2+) regulations are similar in WT and SWAP mice. For equal levels of total NKA inhibition (~25%), ouabain significantly increased Ca(2+) transients (from ΔF/F(0)= 1.5 ± 0.1 to 1.8 ± 0.1), and fractional SR Ca(2+) 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.<br />Conclusion: NKA-α2 has a more prominent role (vs. NKA-α1) in modulating cardiac myocyte SR Ca(2+) release.
- Subjects :
- Animals
Dose-Response Relationship, Drug
Enzyme Inhibitors pharmacology
Isoenzymes
Membrane Potentials
Mice
Mice, Transgenic
Mutation
Myocytes, Cardiac drug effects
Ouabain pharmacology
Sarcoplasmic Reticulum drug effects
Sodium metabolism
Sodium-Calcium Exchanger metabolism
Sodium-Potassium-Exchanging ATPase antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase genetics
Calcium Signaling drug effects
Myocytes, Cardiac enzymology
Sarcoplasmic Reticulum enzymology
Sodium-Potassium-Exchanging ATPase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 95
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 22739122
- Full Text :
- https://doi.org/10.1093/cvr/cvs213