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PMID:10967099

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Citation

Wakimoto, K, Kobayashi, K, Kuro-O, M, Yao, A, Iwamoto, T, Yanaka, N, Kita, S, Nishida, A, Azuma, S, Toyoda, Y, Omori, K, Imahie, H, Oka, T, Kudoh, S, Kohmoto, O, Yazaki, Y, Shigekawa, M, Imai, Y, Nabeshima, Y and Komuro, I (2000) Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. J. Biol. Chem. 275:36991-8

Abstract

Ca(2+), which enters cardiac myocytes through voltage-dependent Ca(2+) channels during excitation, is extruded from myocytes primarily by the Na(+)/Ca(2+) exchanger (NCX1) during relaxation. The increase in intracellular Ca(2+) concentration in myocytes by digitalis treatment and after ischemia/reperfusion is also thought to result from the reverse mode of the Na(+)/Ca(2+) exchange mechanism. However, the precise roles of the NCX1 are still unclear because of the lack of its specific inhibitors. We generated Ncx1-deficient mice by gene targeting to determine the in vivo function of the exchanger. Homozygous Ncx1-deficient mice died between embryonic days 9 and 10. Their hearts did not beat, and cardiac myocytes showed apoptosis. No forward mode or reverse mode of the Na(+)/Ca(2+) exchange activity was detected in null mutant hearts. The Na(+)-dependent Ca(2+) exchange activity as well as protein content of NCX1 were decreased by approximately 50% in the heart, kidney, aorta, and smooth muscle cells of the heterozygous mice, and tension development of the aortic ring in Na(+)-free solution was markedly impaired in heterozygous mice. These findings suggest that NCX1 is required for heartbeats and survival of cardiac myocytes in embryos and plays critical roles in Na(+)-dependent Ca(2+) handling in the heart and aorta.

Links

PubMed Online version:10.1074/jbc.M004035200

Keywords

Animals; Antigens, CD31/chemistry; Antigens, CD31/metabolism; Apoptosis; Arrhythmias, Cardiac/genetics; Exons; Heart/physiology; In Situ Hybridization; Mice; Mice, Mutant Strains; Myocardium/cytology; Placenta/chemistry; Sodium-Calcium Exchanger/genetics; Sodium-Calcium Exchanger/physiology; Yolk Sac/chemistry

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NAC1

involved_in

GO:0098719: sodium ion import across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0044557: relaxation of smooth muscle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0004178)

Seeded From UniProt

complete

MOUSE:NAC1

enables

GO:0005432: calcium:sodium antiporter activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:1901660: calcium ion export

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0051481: negative regulation of cytosolic calcium ion concentration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0014829: vascular associated smooth muscle contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0004178)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0055013: cardiac muscle cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0055074: calcium ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0060402: calcium ion transport into cytosol

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0070509: calcium ion import

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0036376: sodium ion export across plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0071313: cellular response to caffeine

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0000948)

Seeded From UniProt

complete

MOUSE:NAC1

involved_in

GO:0002027: regulation of heart rate

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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