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Robyn T Rebbeck, Maram M Essawy, Florentin R Nitu, Benjamin D Grant, Gregory D Gillispie, David D Thomas, Donald M Bers, Razvan L Cornea
Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca(2+) channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca(2+) regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca(2+)], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders...
October 19, 2016: Journal of Biomolecular Screening
Sungjin Park, Jinhyuk Lee, Yon Hui Kim, Jaheun Park, Jung-Woog Shin, Seungyoon Nam
While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6...
October 6, 2016: Scientific Reports
Hemakumar M Reddy, Kyung-Ah Cho, Monkol Lek, Elicia Estrella, Elise Valkanas, Michael D Jones, Satomi Mitsuhashi, Basil T Darras, Anthony A Amato, Hart Gw Lidov, Catherine A Brownstein, David M Margulies, Timothy W Yu, Mustafa A Salih, Louis M Kunkel, Daniel G MacArthur, Peter B Kang
The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease...
October 6, 2016: Journal of Human Genetics
A F Dulhunty, L Wei-LaPierre, M G Casarotto, N A Beard
The core skeletal muscle ryanodine receptor (RyR1) calcium release complex extends through three compartments of the muscle fibre, linking the extracellular environment through the cytoplasmic junctional gap to the lumen of the internal sarcoplasmic reticulum (SR) calcium store. The protein complex is essential for skeletal excitation-contraction (EC-) coupling and skeletal muscle function. Its importance is highlighted by perinatal death if any one of the EC-coupling components are missing and by myopathies associated with mutation of any of the proteins...
October 1, 2016: Clinical and Experimental Pharmacology & Physiology
Oliver B Clarke, Wayne A Hendrickson
Ryanodine receptors (RyRs) are intracellular cation channels that mediate the rapid and voluminous release of Ca(2+) from the sarcoplasmic reticulum (SR) as required for excitation-contraction coupling in cardiac and skeletal muscle. Understanding of the architecture and gating of RyRs has advanced dramatically over the past two years, due to the publication of high resolution cryo-electron microscopy (cryoEM) reconstructions and associated atomic models of multiple functional states of the skeletal muscle receptor, RyR1...
August 2016: Current Opinion in Structural Biology
N C Voermans, M Snoeck, H Jungbluth
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide spectrum of inherited myopathies presenting throughout life. Malignant hyperthermia susceptibility (MHS)-related RYR1 mutations have emerged as a common cause of exertional rhabdomyolysis, accounting for up to 30% of rhabdomyolysis episodes in otherwise healthy individuals. Common triggers are exercise and heat and, less frequently, viral infections, alcohol and drugs. Most subjects are normally strong and have no personal or family history of malignant hyperthermia...
October 2016: Revue Neurologique
Amédée des Georges, Oliver B Clarke, Ran Zalk, Qi Yuan, Kendall J Condon, Robert A Grassucci, Wayne A Hendrickson, Andrew R Marks, Joachim Frank
The type-1 ryanodine receptor (RyR1) is an intracellular calcium (Ca(2+)) release channel required for skeletal muscle contraction. Here, we present cryo-EM reconstructions of RyR1 in multiple functional states revealing the structural basis of channel gating and ligand-dependent activation. Binding sites for the channel activators Ca(2+), ATP, and caffeine were identified at interdomain interfaces of the C-terminal domain. Either ATP or Ca(2+) alone induces conformational changes in the cytoplasmic assembly ("priming"), without pore dilation...
September 22, 2016: Cell
Kerstin Hoppe, Guido Hack, Frank Lehmann-Horn, Karin Jurkat-Rott, Scott Wearing, Alberto Zullo, Antonella Carsana, Werner Klingler
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism which is characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca(2+) release in myotubes via the ryanodine receptor type 1 (RyR1). As RyR1 is also expressed in B-lymphocytes, this study investigated whether cellular metabolism of native B-lymphocytes was also altered in MH susceptible (MHS) individuals. A potent activator of RyR1, 4-chloro-m-cresol (4-CmC) was used to challenge native B-lymphocytes in a real-time, metabolic assay based on a pH-sensitive silicon biosensor chip...
2016: Scientific Reports
Alexander Polster, Benjamin R Nelson, Eric N Olson, Kurt G Beam
In skeletal muscle, conformational coupling between CaV1.1 in the plasma membrane and type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR) is thought to underlie both excitation-contraction (EC) coupling Ca(2+) release from the SR and retrograde coupling by which RyR1 increases the magnitude of the Ca(2+) current via CaV1.1. Recent work has shown that EC coupling fails in muscle from mice and fish null for the protein Stac3 (SH3 and cysteine-rich domain 3) but did not establish the functional role of Stac3 in the CaV1...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jillian Casey, Karen Flood, Sean Ennis, Emma Doyle, Michael Farrell, Sally Ann Lynch
OBJECTIVE: To determine the underlying molecular aetiology in a non-consanguineous Irish family who have had three fetal losses because of a primary myopathy characterised by fetal akinesia, arthrogryposis multiplex, bilateral pulmonary hypoplasia and reduced muscle bulk. METHODS: Fetal DNA extracted from amniotic cells was whole genome amplified and subjected to whole exome sequencing. RESULTS: Whole exome sequencing identified compound heterozygous variants in RYR1 as the cause of the lethal myopathy in this family...
September 12, 2016: Prenatal Diagnosis
E Wium, A F Dulhunty, N A Beard
Triadin isoforms, splice variants of one gene, maintain healthy Ca(2+) homeostasis in skeletal muscle by subserving several functions including an influence on Ca(2+) release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200-232...
September 5, 2016: Pflügers Archiv: European Journal of Physiology
Takashi Murayama, Nagomi Kurebayashi, Haruo Ogawa, Toshiko Yamazawa, Hideto Oyamada, Junji Suzuki, Kazunori Kanemaru, Katsuji Oguchi, Masamitsu Iino, Takashi Sakurai
Type 1 ryanodine receptor (RYR1) is a Ca(2+) release channel in the sarcoplasmic reticulum of skeletal muscle and is mutated in some muscle diseases, including malignant hyperthermia (MH) and central core disease (CCD). Over 200 mutations associated with these diseases have been identified, and most mutations accelerate Ca(2+) -induced Ca(2+) release (CICR), resulting in abnormal Ca(2+) homeostasis in skeletal muscle. However, it remains largely unknown how specific mutations cause different phenotypes. In this study, we investigated the CICR activity of 14 mutations at 10 different positions in the central region of RYR1 (10 MH and four MH/CCD mutations) using a heterologous expression system in HEK293 cells...
November 2016: Human Mutation
Risheng Wei, Xue Wang, Yan Zhang, Saptarshi Mukherjee, Lei Zhang, Qiang Chen, Xinrui Huang, Shan Jing, Congcong Liu, Shuang Li, Guangyu Wang, Yaofang Xu, Sujie Zhu, Alan J Williams, Fei Sun, Chang-Cheng Yin
Ryanodine receptors (RyRs) are a class of giant ion channels with molecular mass over 2.2 mega-Daltons. These channels mediate calcium signaling in a variety of cells. Since more than 80% of the RyR protein is folded into the cytoplasmic assembly and the remaining residues form the transmembrane domain, it has been hypothesized that the activation and regulation of RyR channels occur through an as yet uncharacterized long-range allosteric mechanism. Here we report the characterization of a Ca(2+)-activated open-state RyR1 structure by cryo-electron microscopy...
September 2016: Cell Research
Angela C Gomez, Timothy W Holford, Naohiro Yamaguchi
Channel activities of skeletal muscle ryanodine receptor (RyR1) are activated by micromolar Ca(2+) and inactivated by higher (~1 mM) Ca(2+) To gain insight into a mechanism underlying Ca(2+)-dependent inactivation of RyR1 and its relationship with skeletal muscle diseases, we constructed nine recombinant RyR1 mutants carrying malignant hyperthermia or centronuclear myopathy associated mutations and determined RyR1 channel activities by [(3)H]ryanodine binding assay. These mutations are localized in or near the RyR1 domains which are responsible for Ca(2+)-dependent inactivation of RyR1...
August 24, 2016: American Journal of Physiology. Cell Physiology
Haidong Yao, Ruifeng Fan, Xia Zhao, Wenchao Zhao, Wei Liu, Jie Yang, Hamid Sattar, Jinxin Zhao, Ziwei Zhang, Shiwen Xu
Selenium (Se) deficiency induces Ca2+ leak and calcification in mammal skeletal muscles; however, the exact mechanism is still unclear. In the present study, both Se-deficient chicken muscle models and selenoprotein W (SelW) gene knockdown myoblast and embryo models were used to study the mechanism. The results showed that Se deficiency-induced typical muscular injuries accompanied with Ca2+ leak and oxidative stress (P < 0.05) injured the ultrastructure of the sarcoplasmic reticulum (SR) and mitochondria; decreased the levels of the Ca2+ channels, SERCA, SLC8A, CACNA1S, ORAI1, STIM1, TRPC1, and TRPC3 (P < 0...
August 20, 2016: Oncotarget
Emily Jane MacKay, Carlos Wilkerson, Natalia Kraeva, Henry Rosenberg, Tara Kennedy
Malignant hyperthermia (MH) remains a diagnostic challenge. This case report describes the anesthetic management of a suspected intraoperative MH episode and the subsequent, genetic sequence analysis of 3 genes associated with MH. The results of the molecular genetic testing revealed heterozygosity for a rare variant, c.12553G>A (p.Ala4185Thr), in the RYR1 gene encoding the ryanodine receptor. Although the RYR1 gene has previously been implicated in the pathogenesis of MH, (1) this particular variant has only been reported in one other case of MH; (2) the role for diagnostic genetic testing in the diagnosis of MH will be examined...
September 2016: Journal of Clinical Anesthesia
Yoshinori Mikami, Kazunori Kanemaru, Yohei Okubo, Takuya Nakaune, Junji Suzuki, Kazuki Shibata, Hiroki Sugiyama, Ryuta Koyama, Takashi Murayama, Akihiro Ito, Toshiko Yamazawa, Yuji Ikegaya, Takashi Sakurai, Nobuhito Saito, Sho Kakizawa, Masamitsu Iino
Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca(2+) release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca(2+) release channel...
September 2016: EBioMedicine
Marta Gaburjakova, Jana Gaburjakova
Ca(2+) plays a critical role in several processes involved in skeletal and cardiac muscle contraction. One key step in cardiac excitation-contraction (E-C) coupling is the activation of the cardiac ryanodine receptor (RYR2) by cytosolic Ca(2+) elevations. Although this process is not critical for skeletal E-C coupling, the activation and inhibition of the skeletal ryanodine receptor (RYR1) seems to be important for overall muscle function. The RYR1 and RYR2 channels fall within the large category of Ca(2+) -binding proteins that harbour highly selective Ca(2+) -binding sites to receive and translate the various Ca(2+) signals into specific functional responses...
August 20, 2016: Acta Physiologica
Heinz Jungbluth, Nicol C Voermans
PURPOSE OF REVIEW: This article reviews adult presentations of the major congenital myopathies - central core disease, multiminicore disease, centronuclear myopathy and nemaline myopathy - with an emphasis on common genetic backgrounds, typical clinicopathological features and differential diagnosis. RECENT FINDINGS: The congenital myopathies are a genetically heterogeneous group of conditions with characteristic histopathological features. Although essentially considered paediatric conditions, some forms - in particular those due to dominant mutations in the skeletal muscle ryanodine receptor (RYR1), the dynamin 2 (DNM2), the amphiphysin 2 (BIN1) and the Kelch repeat-and BTB/POZ domain-containing protein 13 (KBTBD13) gene - may present late into adulthood...
October 2016: Current Opinion in Neurology
Maryline Moulin, Ana Ferreiro
Because of their contractile activity and their high oxygen consumption and metabolic rate, skeletal muscles continually produce moderate levels of reactive oxygen and nitrogen species (ROS/RNS), which increase during exercise and are buffered by multiple antioxidant systems to maintain redox homeostasis. Imbalance between ROS/RNS production and elimination results in oxidative stress (OxS), which has been implicated in aging and in numerous human diseases, including cancer, diabetes or age-related muscle loss (sarcopenia)...
August 12, 2016: Seminars in Cell & Developmental Biology
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