Sodium-calcium exchanger is initially expressed in a heart-restricted pattern within the early mouse embryo

Koushik, Srinagesh V.; Bundy, Justin; Conway, Simon J.

doi:10.1016/s0925-4773(99)00177-x

Cited by 38 publications

(39 citation statements)

References 12 publications

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“…We interpret our results to indicate that the primary purpose of local Ca 2ϩ elevations during diastolic depolarization before an AP is to activate the Na ϩ ͞Ca 2ϩ exchanger, a protein expressed abundantly in early rodent heart and early ES cellderived cardiomyocytes (27,28). The increased inward Na ϩ ͞ Ca 2ϩ exchanger current would accelerate the rate of spontaneous membrane depolarization before an AP (2).…”

Section: Discussionmentioning

confidence: 94%

The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

Huang

Tweedie

Wang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

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In adult myocardium, the heartbeat originates from the sequential activation of ionic currents in pacemaker cells of the sinoatrial node. Ca 2؉ release via the ryanodine receptor (RyR) modulates the rate at which these cells beat. In contrast, the mechanisms that regulate heart rate during early cardiac development are poorly understood. Embryonic stem (ES) cells can differentiate into spontaneously contracting myocytes whose beating rate increases with differentiation time. These cells thus offer an opportunity to determine the mechanisms that regulate heart rate during development. Here we show that the increase in heart rate with differentiation is markedly depressed in ES cell-derived cardiomyocytes with a functional knockout (KO) of the cardiac ryanodine receptor (RyR2). KO myocytes show a slowing of the rate of spontaneous diastolic depolarization and an absence of calcium sparks. The depressed rate of pacemaker potential can be mimicked in wild-type myocytes by ryanodine, and rescued in KO myocytes with herpes simplex virus (HSV)-1 amplicons containing full-length RyR2. We conclude that a functional RyR2 is crucial to the progressive increase in heart rate during differentiation of ES cell-derived cardiomyocytes, consistent with a mechanism that couples Ca 2؉ release via RyR before an action potential with activation of an inward current that accelerates membrane depolarization.

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Section: Discussionmentioning

confidence: 94%

The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

Huang

Tweedie

Wang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

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“…1H). Interestingly, the combined expression patterns of zebrafish NCX1n and NCX1h are comparable to the expression pattern of mammalian NCX1 (23), suggesting that each of these paralogues assumes part of the function of the ancestral NCX1 by subfunctionalization of duplicated genes (22). The distinct expression patterns of NCX1n and NCX1h also suggest that they are involved in different biological processes and that NCX1h has a role in embryonic heart development.…”

Section: Resultsmentioning

confidence: 99%

Mutation in sodium–calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish

Langenbacher

Dong

Shu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium-calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart. calcium homeostasis ͉ cardiac arrhythmia ͉ heart T he heart is a muscular pump that drives circulation throughout the body. It is of the utmost importance to establish rhythmic and synchronized cardiac contraction early in development to ensure proper growth and survival of the embryo.Calcium plays an essential role in regulating cardiac cycles. As a wave of depolarization passes through the heart, a small amount of calcium is permitted to enter the cardiomyocytes through voltage-dependent L-type calcium channels. This small calcium influx then triggers the release of a larger amount of calcium from the sarcoplasmic reticulum via ryanodine receptors, resulting in an abrupt increase in cytosolic calcium levels and cardiac contraction. Relaxation is accomplished by resequestering of calcium to the sarcoplasmic reticulum by sarcoendoplasmic reticular Ca 2ϩ -ATPase2 (SERCA2) and extrusion of calcium from the cell by NCX1 and plasma membrane Ca 2ϩ -ATPase (PMCA). Abnormal calcium handling caused by altered expression levels or protein activities of NCX1 and SERCA2, or by mutations in ryanodine receptors, have been associated with cardiac diseases, such as heart failure and arrhythmia, and with sudden death in humans and animal models (1-6). In addition, genetic studies in the zebrafish demonstrate that L-type calcium channels and the sodium pump (a modulator of NCX activity) are indispensable for embryonic cardiac function (7,8). These findings underscore the critical roles of calcium in embryonic and adult cardiac physiology.Three NCX genes have been identified in mammals. NCX2 and NCX3 are expressed predominantly in the brain and skeletal muscle, respectively, whereas NCX1 is virtually ubiquitous (9). NCX1 is highly expressed in the heart and is considered to be the primary mechanism for calcium extrusion...

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“…Third, in accordance with this result, NCX1 expression was detected in the WT yolk sac and whole embryo. Although NCX1 transcript in the yolk sac was relatively small amount, it was unexpected because Koushik et al reported that NCX1 was expressed in a cardiacspecific pattern within the early mouse embryo until ED 11.0 (Koushik et al, 1999). Wakimoto et al (2001) also reported that alternatively spliced isoforms of NCX1 were expressed in the whole embryo, as well as in the heart of ED 10.5 mice.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Koshik et al showed cardiac restricted NCX1 expression at ED 11.0 using in situ hybridization (Koushik et al, 2001). However, they detected NCX1 in whole embryo at ED 11.0 by PCR analysis (Koushik et al, 1999). Detection by in situ hybridization likely requires that the level of target mRNA within the cell surpasses a concentration threshold (Schneider et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, NCX1 expression is highly restricted to the early embryonic heart and serves an important role in heart development (Koushik et al, 1999;Linask et al, 2001). Moreover, high levels of NCX1 expression and Na + /Ca 2+ exchange activities have also been found in other tissues, such as brain and kidney (reviewed in Friedman, 1998;Sakaue et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

Cho

Lee²,

Shin³

et al. 2003

Exp Mol Med

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The null mutation of cardiac Na + -Ca 2+ exchanger (NCX1) gene in mice caused death of embryo in utero at embryonic day (ED) 9.0-9.5 and this embryonic lethality appears resulted from abnormal heart development. In the present study, we investigated whether transgenic re-expression of NCX1 in mutant cardiac myocytes could rescue these lethal defects. Transgenic mice expressing the canine NCX1 in a cardiac specific manner were bred into the NCX1 knock-out background but did not prevent the fetal lethality associated with the NCX1 null allele. However, the NCX1 knock-out embryos with an NCX1 transgene survived with heart beatings until ED 10.5 which was one day longer than the survival of the NCX1 knock-out embryos (ED 9.5). At ED 10.5, however, the partially rescued NCX1 embryos might have succumbed to the lack of an organized vasculature in the yolk sacs. The placental labyrinth layer was reduced in size and largely avascular. The transgenic re-expression of NCX1 rescued heart beatings and survived longer, but was still insufficient for the mice to be completely rescued. Importantly, NCX1 was observed to express in the yolk sac and the placenta of wild type mice. The results suggest that defects in extra-embryonic compartments are causal to the lethality, and that NCX1 may play an important role in establishing vascularization in extra-em bryonic tissues.

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Sodium-calcium exchanger is initially expressed in a heart-restricted pattern within the early mouse embryo

Cited by 38 publications

References 12 publications

The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development

Mutation in sodium–calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

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