{"title":"Calcium Sparks in the Heart: Dynamics and Regulation.","authors":"Tuan M Hoang-Trong, Aman Ullah, M Saleet Jafri","doi":"10.2147/RRB.S61495","DOIUrl":"https://doi.org/10.2147/RRB.S61495","url":null,"abstract":"<p><p>Calcium (Ca<sup>2+</sup>) plays a central role in the contraction of the heart. It is the bi-directional link between electrical excitation of the heart and contraction. Electrical excitation initiates Ca<sup>2+</sup>influx across the sarcolemma and T-tubular membrane that triggered calcium release from the sarcoplasmic reticulum. Ca<sup>2+</sup>sparks are the elementary events of calcium release from the sarcoplasmic reticulum. Therefore, understanding the dynamics of Ca<sup>2+</sup>sparks is essential for understanding the function of the heart. To this end, numerous experimental and computational studies have focused on this topic, exploring the mechanisms of calcium spark initiation, termination, and regulation and what role these play in normal and patho-physiology. The proper understanding of Ca<sup>2+</sup> spark regulation and dynamics serves as the foundation for our insights into a multitude of pathological conditions may develop that can be the result of structural and/or functional changes at the cellular or subcellular level. Computational modeling of Ca<sup>2+</sup> spark dynamics has proven to be a useful tool to understand Ca<sup>2+</sup> spark dynamics. This review addresses our current understanding of Ca<sup>2+</sup> sparks and how synchronized SR Ca<sup>2+</sup> release, in which Ca<sup>2+</sup> sparks is a major pathway, is linked to the different cardiac diseases, especially arrhythmias.</p>","PeriodicalId":89477,"journal":{"name":"Research and reports in biology","volume":"6 ","pages":"203-214"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/RRB.S61495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34573543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Duchenne muscular dystrophy gene therapy: Lost in translation?","authors":"Dongsheng Duan","doi":"10.2147/RRB.S13463","DOIUrl":"10.2147/RRB.S13463","url":null,"abstract":"<p><p>A milestone of molecular medicine is the identification of dystrophin gene mutation as the cause of Duchenne muscular dystrophy (DMD). Over the last 2 decades, major advances in dystrophin biology and gene delivery technology have created an opportunity to treat DMD with gene therapy. Remarkable success has been achieved in treating dystrophic mice. Several gene therapy strategies, including plasmid transfer, exon skipping, and adeno-associated virus-mediated microdystrophin therapy, have entered clinical trials. However, therapeutic benefit has not been realized in DMD patients. Bridging the gap between mice and humans is no doubt the most pressing issue facing DMD gene therapy now. In contrast to mice, dystrophin-deficient dogs are genetically and phenotypically similar to human patients. Preliminary gene therapy studies in the canine model may offer critical insights that cannot be obtained from murine studies. It is clear that the canine DMD model may represent an important link between mice and humans. Unfortunately, our current knowledge of dystrophic dogs is limited, and the full picture of disease progression remains to be clearly defined. We also lack rigorous outcome measures (such as in situ force measurement) to monitor therapeutic efficacy in dystrophic dogs. Undoubtedly, maintaining a dystrophic dog colony is technically demanding, and the cost of dog studies cannot be underestimated. A carefully coordinated effort from the entire DMD community is needed to make the best use of the precious dog resource. Successful DMD gene therapy may depend on valid translational studies in dystrophin-deficient dogs.</p>","PeriodicalId":89477,"journal":{"name":"Research and reports in biology","volume":"2011 2","pages":"31-42"},"PeriodicalIF":0.0,"publicationDate":"2011-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117615/pdf/nihms278892.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29951620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evgeniy V Petrotchenko, Naohiro Yamaguchi, Daniel A Pasek, Christoph H Borchers, Gerhard Meissner
{"title":"Mass spectrometric analysis and mutagenesis predict involvement of multiple cysteines in redox regulation of the skeletal muscle ryanodine receptor ion channel complex.","authors":"Evgeniy V Petrotchenko, Naohiro Yamaguchi, Daniel A Pasek, Christoph H Borchers, Gerhard Meissner","doi":"10.2147/RRB.S15776","DOIUrl":"10.2147/RRB.S15776","url":null,"abstract":"<p><p>The tetrameric skeletal muscle ryanodine receptor ion channel complex (RyR1) contains a large number of free cysteines that are potential targets for redox-active molecules. Here, we report the mass spectrometric analysis of free thiols in RyR1 using the lipophilic, thiol-specific probe monobromobimane (MBB). In the presence of reduced glutathione, MBB labeled 14 cysteines per RyR1 subunit in tryptic peptides in five of five experiments. Forty-six additional MBB-labeled cysteines per RyR1 subunit were detected with lower frequency in tryptic peptides, bringing the total number of MBB-labeled cysteines to 60 per RyR1 subunit. A combination of fluorescence detection and mass spectrometry of RyR1, labeled in the presence of reduced and oxidized glutathione, identified two redox-sensitive cysteines (C1040 and C1303). Regulation of RyR activity by reduced and oxidized glutathione was investigated in skeletal muscle mutant RyR1s in which 18 cysteines were substituted with serine or alanine, using a [(3)H]ryanodine ligand binding assay. Three single-site RyR1 mutants (C1781S, C2436S, and C2606S) and two multisite mutants with five and seven substituted cysteines exhibited a reduced redox response compared with wild-type RyR1. The results suggest that multiple cysteines determine the redox state and activity of RyR1.</p>","PeriodicalId":89477,"journal":{"name":"Research and reports in biology","volume":" ","pages":"13-21"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095966/pdf/nihms276202.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40101839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jessica L Eisenberg, Asmahan Safi, Xiaoding Wei, Horacio D Espinosa, Gr Scott Budinger, Desire Takawira, Susan B Hopkinson, Jonathan Cr Jones
{"title":"Substrate stiffness regulates extracellular matrix deposition by alveolar epithelial cells.","authors":"Jessica L Eisenberg, Asmahan Safi, Xiaoding Wei, Horacio D Espinosa, Gr Scott Budinger, Desire Takawira, Susan B Hopkinson, Jonathan Cr Jones","doi":"10.2147/RRB.S13178","DOIUrl":"10.2147/RRB.S13178","url":null,"abstract":"<p><p>AIM: The aim of the study was to address whether a stiff substrate, a model for pulmonary fibrosis, is responsible for inducing changes in the phenotype of alveolar epithelial cells (AEC) in the lung, including their deposition and organization of extracellular matrix (ECM) proteins. METHODS: Freshly isolated lung AEC from male Sprague Dawley rats were seeded onto polyacrylamide gel substrates of varying stiffness and analyzed for expression and organization of adhesion, cytoskeletal, differentiation, and ECM components by Western immunoblotting and confocal immunofluorescence microscopy. RESULTS: We observed that substrate stiffness influences cell morphology and the organization of focal adhesions and the actin cytoskeleton. Surprisingly, however, we found that substrate stiffness has no influence on the differentiation of type II into type I AEC, nor does increased substrate stiffness lead to an epithelial-mesenchymal transition. In contrast, our data indicate that substrate stiffness regulates the expression of the α3 laminin subunit by AEC and the organization of both fibronectin and laminin in their ECM. CONCLUSIONS: An increase in substrate stiffness leads to enhanced laminin and fibronectin assembly into fibrils, which likely contributes to the disease phenotype in the fibrotic lung.</p>","PeriodicalId":89477,"journal":{"name":"Research and reports in biology","volume":"2011 2","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510703/pdf/nihms363635.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31093284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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