Ontology highlight
ABSTRACT:
PROVIDER: PRJNA891053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21923443.fastq.gz | Fastqsanger.gz | |||
| SRR21923444.fastq.gz | Fastqsanger.gz | |||
| SRR21923445.fastq.gz | Fastqsanger.gz | |||
| SRR21923446.fastq.gz | Fastqsanger.gz | |||
| SRR21923447.fastq.gz | Fastqsanger.gz |
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Project description:In cardiomyocytes, Ca2+ influx through L-type voltage-gated calcium channels (LTCCs) following membrane depolarization regulates crucial Ca2+-dependent processes including duration and amplitude of the action potentials and excitation-contraction coupling. LTCCs are heteromultimeric proteins composed of the Cav1, Cav, Cav2 and Cav subunits. Here, using ascorbate peroxidase (APEX)-mediated proximity labeling and quantitative proteomics, we identified 61 proteins in the nano-environments of Cav2 in cardiomyocytes. These proteins are involved in diverse cellular functions such as cellular trafficking, muscular contraction, sarcomere organization and excitation-contraction coupling. Moreover, pull-down assays, co-immunoprecipitation analyses and super-resolution imaging using direct stochastic optical reconstruction microscopy (dSTORM) revealed that Cav2 interacts with the ryanodine receptor 2 (RyR2) in adult cardiomyocytes, probably coupling LTCCs and the RyR2 into a supramolecular complex at the dyads. This interaction is mediated by the Src-homology 3 domain of Cav2 and is necessary for an effective pacing frequency‐dependent increase of the Ca2+-induced Ca2+ release mechanism in cardiomyocytes.
2021-12-14 | PXD021375 | Pride
Project description:Cardiac excitation-contraction (E-C) coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse (T)-tubules and junctional sarcoplasmic reticulum (jSR). Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac homeostasis and disease. Here, we used proximity proteomics in intact, living hearts to identify proteins enriched near dyads.
2022-02-21 | PXD028960 | Pride
Project description:Zebrafish hearts can regenerate by replacing damaged tissue with new cardiomyocytes. Although the steps leading up to the proliferation of surviving cardiomyocytes have been extensively studied, little is known about the mechanisms that control proliferation and redifferentiation to a mature state. We found that the cardiac dyad, a structure that regulates calcium handling and excitation-contraction coupling, played a key role in the redifferentiation process. A component of the cardiac dyad called leucine-rich repeat–containing 10 (Lrrc10) acted as a negative regulator of proliferation, prevented cardiomegaly, and induced redifferentiation. We found that its function was conserved in mammalian cardiomyocytes. This study highlights the importance of the underlying mechanisms required for heart regeneration and their application to the generation of fully functional cardiomyocytes.
2023-05-19 | GSE224156 | GEO
Project description:Junctophilin-2 (JP2) is an essential component of the excitation-contraction coupling apparatus in cardiomyocytes and becomes proteolytically cleaved in response to stress. We previously mapped the primary calpain cleavage site to JP2 residues 565-566 using in vitro assays. To determine whether this site is responsible for JP2 cleavage in vivo, we generated calpain resistant JP2 (JP2CR) knock-in mice lacking this site. We find JP2 is not cleaved in JP2CR mice during pressure overload stress resulting in better cardiac outcomes and an attenuated transcriptional response relative to wildtype mice.
2024-08-01 | GSE235601 | GEO
Project description:Our aim is to analyze how does the lack of each of the Ca2+ channels, involved in excitation-contraction coupling in skeletal muscle - RYR1 and Cav1.1, affect gene expression in embryonic mouse limb skeletal muscle during secondary myogenesis. We extracted total RNA from the limb skeletal muscle of WT, heterozygous RYR1-/+ and Cav1.1+/-, and homozygous RYR1-/- and Cav1.1-/- mutants from 3 litters (n = 3 for each group) at days E14.5 and E18.5 and subjected it to microarray analyses.
2017-11-24 | E-MTAB-5755 | biostudies-arrayexpress
Project description:Calpains are calcium (Ca2+) activated neutral proteases that are involved in several essential signaling pathways. One Calpain-specific proteolytic target is Junctophilin-2 (JP2), an important structural protein of Ca2+ release units required for the excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in mouse models of heart failure has been reported previously, the precise molecular identity of the Calpain cleavage sites and the (patho-) physiological roles of the JP2 proteolytic products remain controversial. We systematically analyzed the JP2 cleavage fragments as function of Calpain-1 versus Calpain-2 proteolytic activities, revealing that both Calpain isoforms preferentially cleave mouse JP2 at R565, but subsequently also at three additional secondary Calpain cleavage sites. We identified the Calpain-specific primary cleavage products not only in mouse but also in human iPSC-derived cardiomyocytes (hiPSC-CMs). Knockout of RyR2 in hiPSC-CMs destabilized JP2 resulting in an increase of the Calpain-specifc cleavage fragments. The primary N-terminal cleavage product (NT1) accumulated in the nucleus of mouse and human cardiomyocytes in a Ca2+ dependent manner, closely associated with DNA-rich chromosomal regions, where NT1 is proposed to function as a cardioprotective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.
2022-08-12 | PXD031424 | Pride
Project description:Calpains are calcium (Ca2+) activated neutral proteases that are involved in several essential signaling pathways. One Calpain-specific proteolytic target is Junctophilin-2 (JP2), an important structural protein of Ca2+ release units required for the excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in mouse models of heart failure has been reported previously, the precise molecular identity of the Calpain cleavage sites and the (patho-) physiological roles of the JP2 proteolytic products remain controversial. We systematically analyzed the JP2 cleavage fragments as function of Calpain-1 versus Calpain-2 proteolytic activities, revealing that both Calpain isoforms preferentially cleave mouse JP2 at R565 but subsequently also at three additional secondary Calpain cleavage sites. We identified the Calpain-specific primary cleavage products not only in mouse but also in human iPSC-derived cardiomyocytes (hiPSC-CMs). Knockout of RyR2 in hiPSC-CMs destabilized JP2 resulting in an increase of the Calpain-specifc cleavage fragments. The primary N-terminal cleavage product (NT1) accumulated in the nucleus of mouse and human cardiomyocytes in a Ca2+ dependent manner, closely associated with DNA-rich chromosomal regions, where NT1 is proposed to function as a cardioprotective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.
2022-08-12 | PXD031321 | Pride
Project description:Chromatin remodelling provides a key mechanism for the regulation of gene expression through dynamic alterations in nucleosome occupancy at promoters and enhancers. Haploinsufficiency for the ATP-dependent chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7) causes human CHARGE syndrome. CHARGE is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations, and has traditionally been considered a neurocristopathy. We present a new perspective, by showing severe structural cardiovascular defects following ablation of Chd7 in the anterior mesoderm and other cardiac-related lineages. We identify multiple downstream pathways affected by the loss of Chd7 and disruption of excitation-contraction coupling in cardiomyocytes. Furthermore, we demonstrate CHD7 binding at the Sema3C promoter and alterations to the local chromatin structure in vivo, indicating direct transcriptional regulation. This work therefore provides novel insights into the etiology of heart defects arising in CHARGE syndrome and reveals a requirement for CHD7 activity in mesodermal cardiac progenitors.
2015-06-30 | GSE59963 | GEO
Project description:Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this novel role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.
2021-03-09 | GSE168487 | GEO
Project description:Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signalâs secondary function in the activity-dependent regulation of fiber type composition. Differential gene expression between soleus and EDL muscle fibres from wildtype and Cav1.1 delta E29 mice.
2016-04-01 | E-GEOD-67803 | biostudies-arrayexpress