The Cardiac Na
            <sup>+</sup>
            ‐Ca
            <sup>2+</sup>
            Exchanger: From Structure to Function

Ottolia, Michela; John, Scott A.; Hazan, Adina; Goldhaber, Joshua I.

doi:10.1002/cphy.c200031

Cited by 20 publications

(18 citation statements)

References 296 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cardiac structural remodeling is inevitably accompanied by electrophysiological changes. To evaluate these changes, we studied several Ca 2+ ‐handling genes, that is, gap junction protein 1 ( Gja1 also known as connexin 43, Figure 8a), aquaporin 1 ( Aqp1 , Figure 8b), aquaporin 7 ( Aqp7 , Figure 8c), ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2 ( Atp2a2 , Figure 8d), solute carrier family 8 member A1 ( Slc8a1 , Figure 8e) to get an insight into the electrophysiology‐managing genes of the heart (Butler et al, 2006; Nakamura & Sadoshima, 2018; Ottolia et al, 2021; Severs, 2001; Verkerk et al, 2019). The expression of Gja1 was significantly upregulated ( p < 0.05) while Aqp1 was significantly downregulated ( p < 0.05) in TS mice.…”

Section: Resultsmentioning

confidence: 99%

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

Rojo‐García

Vanmunster

Pacolet

et al. 2023

Physiological Reports

View full text Add to dashboard Cite

Sedentary behavior has become ingrained in our society and has been linked to cardiovascular diseases. Physical inactivity is the main characteristic of sedentary behavior. However, its impact on cardiovascular disease is not clear. Therefore, we investigated the effect of physical inactivity in an established mouse model on gene clusters associated with cardiac fibrosis, electrophysiology, cell regeneration, and tissue degradation/turnover. We investigated a sedentary group (CTR, n = 10) versus a tail suspension group (TS, n = 11) that caused hindlimb unloading and consequently physical inactivity. Through histological, protein content, and transcript analysis approaches, we found that cardiac fibrosis‐related genes partly change, with significant TS‐associated increases in Tgfb1, but without changes in Col1a1 and Fn1. These changes are not translated into fibrosis at tissue level. We further detected TS‐mediated increases in protein degradation‐ (Trim63, p < 0.001; Fbxo32, p = 0.0947 as well as in biosynthesis‐related [P70s6kb1, p < 0.01]). Corroborating these results, we found increased expression of autophagy markers such as Atg7 (p < 0.01) and ULK1 (p < 0.05). Two cardiomyocyte regeneration‐ and sarcomerogenesis‐related genes, Yap (p = 0.0535) and Srf (p < 0.001), increased upon TS compared to CTR conditions. Finally, we found significant upregulation of Gja1 (p < 0.05) and a significant downregulation of Aqp1 (p < 0.05). Our data demonstrate that merely 2 weeks of reduced physical activity induce changes in genes associated with cardiac structure and electrophysiology. Hence, these data should find the basis for novel research directed to evaluate the interplay of cardiac functioning and physical inactivity.

show abstract

Section: Resultsmentioning

confidence: 99%

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

Rojo‐García

Vanmunster

Pacolet

et al. 2023

Physiological Reports

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

“…This list includes several genes that are integral to heart development or function including RBFOX2, SLC8A1, and MYBPC3. 24,75,78 It remains possible that a greater number of ortholog pairs exist but some evaded detection. This could be due to experimental constraints such as having to perform RNA-sequencing on whole embryos rather than isolated hearts.…”

Section: Discussionmentioning

confidence: 99%

“…75 Another mis-spliced myocardial gene was sslc8a1a (solute carrier family 8 member 1a; previously named ncx1 [sodium-calcium exchanger 1]) which encodes a plasma membrane transporter responsible for extruding calcium from cardiomyocytes during cardiac relaxation. [76][77][78] In the case of mybpc3, exons 2 and exons 10 were identified as cassette exons whose inclusion levels (Inclevels) in mature mybpc3 transcripts were found to be significantly lower in rbpms2-null animals, as evidenced by positive Inclevel differences where Incleveldifference=Inc level control -Inclevel rbpms2-null (Figure 3B; Table S4). The same was true for exon 16 of myom2a and exon 5 of slc8a1a (Figure 3B; Table S4).…”

Section: Identification Of Differential Alternative Splicing Events I...mentioning

confidence: 99%

See 1 more Smart Citation

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

Akerberg

Trembley

Butty

et al. 2022

Circulation Research

View full text Add to dashboard Cite

Background: RBPs (RNA-binding proteins) perform indispensable functions in the post-transcriptional regulation of gene expression. Numerous RBPs have been implicated in cardiac development or physiology based on gene knockout studies and the identification of pathogenic RBP gene mutations in monogenic heart disorders. The discovery and characterization of additional RBPs performing indispensable functions in the heart will advance basic and translational cardiovascular research. Methods: We performed a differential expression screen in zebrafish embryos to identify genes enriched in nkx2.5 -positive cardiomyocytes or cardiopharyngeal progenitors compared to nkx2.5 -negative cells from the same embryos. We investigated the myocardial-enriched gene RNA-binding protein with multiple splicing (variants) 2 [ RBPMS2 )] by generating and characterizing rbpms2 knockout zebrafish and human cardiomyocytes derived from RBPMS2 -deficient induced pluripotent stem cells. Results: We identified 1848 genes enriched in nkx2.5 -positive population. Among the most highly enriched genes, most with well-established functions in the heart, we discovered the ohnologs rbpms2a and rbpms2b , which encode an evolutionarily conserved RBP. Rbpms2 localizes selectively to cardiomyocytes during zebrafish heart development and strong cardiomyocyte expression persists into adulthood. Rbpms2-deficient embryos suffer from early cardiac dysfunction characterized by reduced ejection fraction. The functional deficit is accompanied by myofibril disarray, altered calcium handling, and differential alternative splicing events in mutant cardiomyocytes. These phenotypes are also observed in RBPMS2 -deficient human cardiomyocytes, indicative of conserved molecular and cellular function. RNA-sequencing and comparative analysis of genes mis-spliced in RBPMS2 -deficient zebrafish and human cardiomyocytes uncovered a conserved network of 29 ortholog pairs that require RBPMS2 for alternative splicing regulation, including RBFOX2 , SLC8A1 , and MYBPC3 . Conclusions: Our study identifies RBPMS2 as a conserved regulator of alternative splicing, myofibrillar organization, and calcium handling in zebrafish and human cardiomyocytes.

show abstract

“…Cardiac function relies on the precise quantitative control of both the temporal and spatial distribution of intracellular Ca 2+ . While many proteins contribute to this process, the plasma membrane Na + -Ca 2+ exchanger (NCX1) has been recognized as one of the most influential within this group of Ca 2+ -controlling proteins 1 – 4 . NCX1 moves Ca 2+ out of the cell, against its gradient, by harnessing the energy stored in the electrochemical gradient of Na + as a driving force.…”

Section: Introductionmentioning

confidence: 99%

Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1

Scranton,

John,

Angelini

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

show abstract

The Cardiac Na ⁺ ‐Ca ²⁺ Exchanger: From Structure to Function

Cited by 20 publications

References 296 publications

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1

Contact Info

Product

Resources

About

The Cardiac Na + ‐Ca 2+ Exchanger: From Structure to Function

Cited by 20 publications

References 296 publications

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1

Contact Info

Product

Resources

About

The Cardiac Na ⁺ ‐Ca ²⁺ Exchanger: From Structure to Function