Document Detail


Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes.
MedLine Citation:
PMID:  22739122     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Sanda Despa; Jerry B Lingrel; Donald M Bers
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-27
Journal Detail:
Title:  Cardiovascular research     Volume:  95     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-01-08     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  480-6     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of California at Davis, Genome Building Rm 3513, Davis, CA 95616-8636, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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
Comments/Corrections

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