| Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes. | |
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MedLine Citation:
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PMID: 22739122 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. 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. CONCLUSION: NKA-α2 has a more prominent role (vs. NKA-α1) in modulating cardiac myocyte SR Ca(2+) release. |
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Authors:
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Sanda Despa; Jerry B Lingrel; Donald M Bers |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-06-27 |
Journal Detail:
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Title: Cardiovascular research Volume: 95 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-08-20 Completed Date: 2013-01-08 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
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Languages: eng Pagination: 480-6 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of California at Davis, Genome Building Rm 3513, Davis, CA 95616-8636, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium Signaling* / drug effects Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Isoenzymes Membrane Potentials Mice Mice, Transgenic Mutation Myocytes, Cardiac / drug effects, enzymology* Ouabain / pharmacology Sarcoplasmic Reticulum / drug effects, enzymology* Sodium / metabolism Sodium-Calcium Exchanger / metabolism Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors, genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL109501/HL/NHLBI NIH HHS; HL28573/HL/NHLBI NIH HHS; HL81526/HL/NHLBI NIH HHS; R01 HL030077/HL/NHLBI NIH HHS; R01 HL109501/HL/NHLBI NIH HHS; R37 HL030077/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Isoenzymes; 0/Sodium-Calcium Exchanger; 630-60-4/Ouabain; 7440-23-5/Sodium; EC 3.6.1.-/Atp1a2 protein, mouse; EC 3.6.3.9/Atp1a1 protein, mouse; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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