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Julia O Reynolds, Ann P Quick, Qiongling Wang, David L Beavers, Leonne E Philippen, Jordan Showell, Giselle Barreto-Torres, Donna J Thuerauf, Shirin Doroudgar, Christopher C Glembotski, Xander H T Wehrens
BACKGROUND: Junctophilin-2 (JPH2) is the primary structural protein for the coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes (JMCs) in cardiomyocytes. Effective signaling between these channels ensures adequate Ca-induced Ca release required for normal cardiac contractility. Disruption of JMC subcellular domains, a common feature of failing hearts, has been attributed to JPH2 downregulation...
October 8, 2016: International Journal of Cardiology
Ann P Quick, Qiongling Wang, Leonne E Philippen, Giselle Barreto-Torres, David Y Chiang, David L Beavers, Guoliang Wang, Maha Khalid, Julia O Reynolds, Hannah M Campbell, Jordan Showell, Mark D McCauley, Arjen Scholten, Xander H Wehrens
RATIONALE: Junctional membrane complexes (JMC) in myocytes are critical microdomains, in which excitation-contraction coupling occurs. Structural and functional disruption of JMCs underlies contractile dysfunction in failing hearts. However, the role of newly identified JMC protein striated muscle preferentially expressed gene (SPEG) remains unclear. OBJECTIVE: To determine the role of SPEG in healthy and failing adult hearts. MMethods and Results: Proteomic analysis of immunoprecipatated JMC-proteins ryanodine receptor type-2 (RyR2) and junctophilin-2 (JPH2) followed by mass spectrometry identified the serine-threonine kinase SPEG as the only novel binding partner for both proteins...
October 11, 2016: Circulation Research
M Sabater-Molina, M Navarro, E García-Molina Sáez, I Garrido, D Pascual-Figal, J González Carrillo, J R Gimeno Blanes
No abstract text is available yet for this article.
July 29, 2016: Clinical Genetics
Qian Zhang, Wenyu Gou, Xiaotong Wang, Yawen Zhang, Jun Ma, Hongliang Zhang, Ying Zhang, Hao Zhang
Tibetan chicken, unlike their lowland counterparts, exhibit specific adaptations to high-altitude conditions. The genetic mechanisms of such adaptations in highland chickens were determined by resequencing the genomes of four highland (Tibetan and Lhasa White) and four lowland (White Leghorn, Lindian, and Chahua) chicken populations. Our results showed an evident genetic admixture in Tibetan chickens, suggesting a history of introgression from lowland gene pools. Genes showing positive selection in highland populations were related to cardiovascular and respiratory system development, DNA repair, response to radiation, inflammation, and immune responses, indicating a strong adaptation to oxygen scarcity and high-intensity solar radiation...
March 2016: Genome Biology and Evolution
Carolina Bongini, Cecilia Ferrantini, Francesca Girolami, Raffaele Coppini, Anna Arretini, Mattia Targetti, Sara Bardi, Gabriele Castelli, Francesca Torricelli, Franco Cecchi, Michael J Ackerman, Luigi Padeletti, Corrado Poggesi, Iacopo Olivotto
Genes associated with hypertrophic cardiomyopathy (HC) are not uniformly expressed in the atrial myocardium. Whether this may impact susceptibility to atrial fibrillation (AF) is unresolved. To analyze the prevalence and clinical correlates of AF in relation to genotype in a large HC cohort, prevalence and clinical profile of AF were assessed in 237 patients with HC, followed for 14 ± 10 years. Patients were divided into 3 genetic subgroups: (1) MYBPC3 (58%), (2) MYH7 (28%), and (3) "other genotypes" (14%; comprising TNNT2, TNNI3, TPM1, MYL2, complex genotypes, Z-line, and E-C coupling genes)...
April 1, 2016: American Journal of Cardiology
Virginia Barone, Davide Randazzo, Valeria Del Re, Vincenzo Sorrentino, Daniela Rossi
The sarcoplasmic reticulum (SR) of striated muscles is specialized for releasing Ca(2+) following sarcolemma depolarization in order to activate muscle contraction. To this end, the SR forms a network of longitudinal tubules and cisternae that surrounds the myofibrils and, at the same time, participates to the assembly of the triadic junctional membrane complexes formed by the close apposition of one t-tubule, originated from the sarcolemma, and two SR terminal cisternae. Advancements in understanding the molecular basis of the SR structural organization have identified an interaction between sAnk1, a transmembrane protein located on the longitudinal SR (l-SR) tubules, and obscurin, a myofibrillar protein...
December 2015: Journal of Muscle Research and Cell Motility
Yufeng Hou, Isuru Jayasinghe, David J Crossman, David Baddeley, Christian Soeller
The contractile properties of cardiac myocytes depend on the calcium (Ca(2+)) released by clusters of ryanodine receptors (RyRs) throughout the myoplasm. Accurate quantification of the spatial distribution of RyRs has previously been challenging due to the comparatively low resolution in optical microscopy. We have combined single-molecule localisation microscopy (SMLM) in a super-resolution modality known as dSTORM with immunofluorescence staining of tissue sections of rat ventricles to resolve a wide, near-exponential size distribution of RyR clusters that lined on average ~57% of the perimeter of each myofibril...
March 2015: Journal of Molecular and Cellular Cardiology
Nupoor Narula, David J Tester, Anna Paulmichl, Joseph J Maleszewski, Michael J Ackerman
Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes...
April 2015: Pediatric Cardiology
Masaru Katoh
Cardiovascular diseases and cancers are the leading causes of morbidity and mortality in the world. MicroRNAs (miRNAs) are short non-coding RNAs that primarily repress target mRNAs. Here, miR-24, miR-125b, miR-195, and miR-214 were selected as representative cardio-miRs that are upregulated in human heart failure. To bridge the gap between miRNA studies in cardiology and oncology, the targets and functions of these miRNAs in cardiovascular diseases and cancers will be reviewed. ACVR1B, BCL2, BIM, eNOS, FGFR3, JPH2, MEN1, MYC, p16, and ST7L are miR-24 targets that have been experimentally validated in human cells...
2014: Frontiers in Cell and Developmental Biology
Wei Wang, Andrew P Landstrom, Qiongling Wang, Michelle L Munro, David Beavers, Michael J Ackerman, Christian Soeller, Xander H T Wehrens
Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca(2+) leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca(2+) release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca(2+) imaging...
November 1, 2014: American Journal of Physiology. Heart and Circulatory Physiology
Isuru D Jayasinghe, Michelle Munro, David Baddeley, Bradley S Launikonis, Christian Soeller
Localization microscopy is a fairly recently introduced super-resolution fluorescence imaging modality capable of achieving nanometre-scale resolution. We have applied the dSTORM variation of this method to image intracellular molecular assemblies in skeletal muscle fibres which are large cells that critically rely on nanoscale signalling domains, the triads. Immunofluorescence staining in fixed adult rat skeletal muscle sections revealed clear differences between fast- and slow-twitch fibres in the molecular organization of ryanodine receptors (RyRs; the primary calcium release channels) within triads...
October 6, 2014: Journal of the Royal Society, Interface
David L Beavers, Andrew P Landstrom, David Y Chiang, Xander H T Wehrens
Cardiomyocytes rely on a highly specialized subcellular architecture to maintain normal cardiac function. In a little over a decade, junctophilin-2 (JPH2) has become recognized as a cardiac structural protein critical in forming junctional membrane complexes (JMCs), which are subcellular domains essential for excitation-contraction coupling within the heart. While initial studies described the structure of JPH2 and its role in anchoring junctional sarcoplasmic reticulum and transverse-tubule (T-tubule) membrane invaginations, recent research has an expanded role of JPH2 in JMC structure and function...
July 15, 2014: Cardiovascular Research
Jun Zhang, Xianwei Cui, Yahui Shen, Lingxia Pang, Aiqing Zhang, Ziyi Fu, Jiantao Chen, Xirong Guo, Weihua Gan, Chenbo Ji
Both brown adipose tissue and skeletalmuscle have abundant mitochondria and energy consumption capacity. They are similar in origin and gain different potential of energy metabolism after differentiation and maturation. The mechanism that cause the difference is not yet fully understood. Long non-coding RNAs (lncRNAs) which comprise the bulk of the human non-coding transcriptome have been proved to play key roles in various biological processes. Whether they will have a function on the differentiation and energy metabolism between BAT and skeletalmuscle is still unknown...
January 17, 2014: Biochemical and Biophysical Research Communications
David L Beavers, Wei Wang, Sameer Ather, Niels Voigt, Alejandro Garbino, Sayali S Dixit, Andrew P Landstrom, Na Li, Qiongling Wang, Iacopo Olivotto, Dobromir Dobrev, Michael J Ackerman, Xander H T Wehrens
OBJECTIVES: This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF). BACKGROUND: JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels (RyR2). Whereas defective RyR2-mediated Ca(2+) release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias. METHODS: Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF)...
November 19, 2013: Journal of the American College of Cardiology
Julia O Reynolds, David Y Chiang, Wei Wang, David L Beavers, Sayali S Dixit, Darlene G Skapura, Andrew P Landstrom, Long-Sheng Song, Michael J Ackerman, Xander H T Wehrens
AIMS: Transverse tubules (TTs) provide the basic subcellular structures that facilitate excitation-contraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within the first few weeks of life in mammals but the molecular determinants of this development have remained elusive. This study aims to elucidate the role of junctophilin-2 (JPH2), a junctional membrane complex protein, in the maturation of TTs in cardiomyocytes...
October 1, 2013: Cardiovascular Research
Ben Davidson, Vera Maria Abeler, Ellen Hellesylt, Arild Holth, Ie-Ming Shih, Tone Skeie-Jensen, Li Chen, Yanqin Yang, Tian-Li Wang
OBJECTIVE: Endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) are the two most common uterine sarcomas, but both are rare tumors. The aim of the present study was to compare the global gene expression patterns of ESS and LMS. METHODS: Gene expression profiles of 7 ESS and 13 LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. RESULTS: Unsupervised hierarchical clustering using all 54,675 genes in the array separated ESS from LMS samples...
February 2013: Gynecologic Oncology
A P Landstrom, M J Ackerman
Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM...
June 2012: Current Molecular Medicine
Ralph J van Oort, Alejandro Garbino, Wei Wang, Sayali S Dixit, Andrew P Landstrom, Namit Gaur, Angela C De Almeida, Darlene G Skapura, Yoram Rudy, Alan R Burns, Michael J Ackerman, Xander H T Wehrens
BACKGROUND: Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process in the heart...
March 8, 2011: Circulation
Andrew P Landstrom, Cherisse A Kellen, Sayali S Dixit, Ralph J van Oort, Alejandro Garbino, Noah Weisleder, Jianjie Ma, Xander H T Wehrens, Michael J Ackerman
BACKGROUND: Junctophilin-2 (JPH2), a protein expressed in the junctional membrane complex, is necessary for proper intracellular calcium (Ca(2+)) signaling in cardiac myocytes. Downregulation of JPH2 expression in a model of cardiac hypertrophy was recently associated with defective coupling between plasmalemmal L-type Ca(2+) channels and sarcoplasmic reticular ryanodine receptors. However, it remains unclear whether JPH2 expression is altered in patients with hypertrophic cardiomyopathy (HCM)...
March 2011: Circulation. Heart Failure
Alejandro Garbino, Xander H T Wehrens
Junctophilin-2 (JPH2) is a membrane-binding protein that plays a key role in the organization of the junctional membrane complex (JMC) in cardiac myocytes. JPH2 is believed to keep the plasma membrane and sarcoplasmic reticulum at a fixed distance within the JMC, which is essential for proper Ca(2+)-induced Ca(2+) release during the excitation-contraction process. Recent studies have revealed that mutations in the JPH2 gene are associated with hypertrophic cardiomyopathy, highlighting the importance of this protein for normal cardiac physiology...
September 2010: Acta Pharmacologica Sinica
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