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[PMID]:29178655
[Au] Autor:Laughlin RS; Niu Z; Wieben E; Milone M
[Ad] Endereço:Department of Neurology, Mayo Clinic, Rochester, Minnesota.
[Ti] Título:RYR1 causing distal myopathy.
[So] Source:Mol Genet Genomic Med;5(6):800-804, 2017 11.
[Is] ISSN:2324-9269
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Congenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness. METHODS: We report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene. RESULTS: The patient manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face in addition to limited jaw opening. Creatine kinase was mildly elevated with EMG findings supporting a myopathy. Muscle biopsy showed features consistent with centronuclear myopathy. Whole exome sequencing revealed a novel heterozygous pathogenic variant in RYR1 (c.12315_12328delAGAAATCCAGTTCC, p.Glu4106Alafs*8), and a heterozygous missense variant (c.10648C>T, p.Arg3550Trp) of unknown significance in compound heterozygous state. CONCLUSION: We expand the spectrum of RYR1-related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies.
[Mh] Termos MeSH primário: Miopatias Distais/genética
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Mh] Termos MeSH secundário: Adulto
Creatina Quinase/metabolismo
Análise Mutacional de DNA
Miopatias Distais/diagnóstico
Eletromiografia
Heterozigoto
Seres Humanos
Anormalidades Maxilomandibulares/fisiopatologia
Masculino
Músculo Esquelético/patologia
Linhagem
Fenótipo
Polimorfismo de Nucleotídeo Único
Extremidade Superior/fisiopatologia
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ryanodine Receptor Calcium Release Channel); EC 2.7.3.2 (Creatine Kinase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/mgg3.338


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[PMID]:28465322
[Au] Autor:Michelucci A; Paolini C; Boncompagni S; Canato M; Reggiani C; Protasi F
[Ad] Endereço:Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d'Annunzio, Chieti, Italy.
[Ti] Título:Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.
[So] Source:FASEB J;31(8):3649-3662, 2017 08.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1 ) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1 and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1 and CASQ1-null mice, respectively, 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1 and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca -dependent activation of calpains and NF-κB by lowering myoplasmic Ca concentration and nitro-oxidative stress, parameters that were elevated in RYR1 and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.-Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.
[Mh] Termos MeSH primário: Proteínas de Ligação ao Cálcio/metabolismo
Hipertermia Maligna/patologia
Condicionamento Físico Animal
Esforço Físico
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
[Mh] Termos MeSH secundário: Animais
Cafeína/farmacologia
Proteínas de Ligação ao Cálcio/genética
Estimulação Elétrica
Regulação da Expressão Gênica/fisiologia
Predisposição Genética para Doença
Hipertermia Maligna/genética
Camundongos
Camundongos Knockout
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/fisiologia
Rabdomiólise
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Casq1 protein, mouse); 0 (Ryanodine Receptor Calcium Release Channel); 3G6A5W338E (Caffeine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601292R


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[PMID]:27771553
[Au] Autor:Kato T; Yamamoto T; Nakamura Y; Nanno T; Fukui G; Sufu Y; Hamada Y; Maeda T; Nishimura S; Ishiguchi H; Murakami W; Fukuda M; Xu X; Hino A; Ono M; Oda T; Okuda S; Kobayashi S; Koseki N; Kyushiki H; Yano M
[Ad] Endereço:Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
[Ti] Título:Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure.
[So] Source:Heart Rhythm;14(1):120-127, 2017 01.
[Is] ISSN:1556-3871
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR). OBJECTIVE: The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure. METHODS: Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle. RESULTS: TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca transients in TAC cells during and after 1-5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM. CONCLUSION: Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca leakage, delayed afterdepolarization, triggered activity, Ca spark frequency, spontaneous Ca transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.
[Mh] Termos MeSH primário: Calmodulina/metabolismo
Insuficiência Cardíaca/diagnóstico por imagem
Insuficiência Cardíaca/terapia
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Taquicardia Ventricular/diagnóstico
[Mh] Termos MeSH secundário: Animais
Mapeamento Potencial de Superfície Corporal/métodos
Canais de Cálcio/metabolismo
Sinalização do Cálcio
Células Cultivadas
Modelos Animais de Doenças
Insuficiência Cardíaca/mortalidade
Camundongos
Camundongos Endogâmicos
Miócitos Cardíacos/metabolismo
Distribuição Aleatória
Valores de Referência
Retículo Sarcoplasmático/metabolismo
Sensibilidade e Especificidade
Taquicardia Ventricular/mortalidade
Taquicardia Ventricular/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Calcium Channels); 0 (Calmodulin); 0 (Ryanodine Receptor Calcium Release Channel)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180121
[Lr] Data última revisão:
180121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:29173400
[Au] Autor:Schwartz PJ; Ackerman MJ; Wilde AAM
[Ad] Endereço:Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, c/o Centro Diagnostico e di Ricerca S. Carlo, Via Pier Lombardo, 22, Milan 20135, Italy. Electronic address: peter.schwartz@unipv.it.
[Ti] Título:Channelopathies as Causes of Sudden Cardiac Death.
[So] Source:Card Electrophysiol Clin;9(4):537-549, 2017 Dec.
[Is] ISSN:1877-9190
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This article reviews the main clinical aspects of 3 channelopathies: the long QT syndrome, the catecholaminergic polymorphic ventricular tachycardia, and the Brugada syndrome. The text summarizes our views on clinical presentation and diagnosis, on risk stratification, and on therapy. Special attention is given to the progress in the understanding of the genetic bases and on the growing impact of genetics on therapy, which, at least in the case of long QT syndrome, now allows gene-specific management.
[Mh] Termos MeSH primário: Arritmias Cardíacas/genética
Canalopatias/genética
Morte Súbita Cardíaca
[Mh] Termos MeSH secundário: Seres Humanos
Risco
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Ryanodine Receptor Calcium Release Channel)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:29037160
[Au] Autor:Uysal F; Turkgenc B; Toksoy G; Bostan OM; Evke E; Uyguner O; Yakicier C; Kayserili H; Cil E; Temel SG
[Ad] Endereço:Department of Pediatric Cardiology, University of Uludag, School of Medicine, Bursa, Turkey.
[Ti] Título:"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports".
[So] Source:BMC Med Genet;18(1):114, 2017 Oct 16.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients. CASE PRESENTATIONS: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. ß-blocker therapy was initiated to all the index subjects. CONCLUSIONS: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations.
[Mh] Termos MeSH primário: Perda Auditiva Neurossensorial/congênito
Síndrome de Jervell-Lange Nielsen/genética
Canal de Potássio KCNQ1/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/uso terapêutico
Pré-Escolar
Eletrocardiografia
Feminino
Perda Auditiva Neurossensorial/etiologia
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Proteína Homeobox Nkx-2.5/genética
Homozigoto
Seres Humanos
Lactente
Síndrome de Jervell-Lange Nielsen/diagnóstico
Síndrome de Jervell-Lange Nielsen/tratamento farmacológico
Masculino
Linhagem
Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
Análise de Sequência de DNA/métodos
Turquia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Homeobox Protein Nkx-2.5); 0 (KCNE1 protein, human); 0 (KCNQ1 Potassium Channel); 0 (KCNQ1 protein, human); 0 (NKX2-5 protein, human); 0 (Potassium Channels, Voltage-Gated); 0 (RyR2 protein, human); 0 (Ryanodine Receptor Calcium Release Channel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0474-8


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[PMID]:28961276
[Au] Autor:Liu Y; Wei J; Wong King Yuen SM; Sun B; Tang Y; Wang R; Van Petegem F; Chen SRW
[Ad] Endereço:Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
[Ti] Título:CPVT-associated cardiac ryanodine receptor mutation G357S with reduced penetrance impairs Ca2+ release termination and diminishes protein expression.
[So] Source:PLoS One;12(9):e0184177, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most lethal inherited cardiac arrhythmias mostly linked to cardiac ryanodine receptor (RyR2) mutations with high disease penetrance. Interestingly, a novel RyR2 mutation G357S discovered in a large family of more than 1400 individuals has reduced penetrance. The molecular basis for the incomplete disease penetrance in this family is unknown. To gain insights into the variable disease expression in this family, we determined the impact of the G357S mutation on RyR2 function and expression. We assessed spontaneous Ca2+ release in HEK293 cells expressing RyR2 wildtype and the G357S mutant during store Ca2+ overload, also known as store overload induced Ca2+ release (SOICR). We found that the G357S mutation reduced the percentage of RyR2-expressing cells that showed SOICR. However, in cells that displayed SOICR, G357S reduced the thresholds for the activation and termination of SOICR. Furthermore, G357S decreased the thermal stability of the N-terminal domain of RyR2, and markedly reduced the protein expression of the full-length RyR2. On the other hand, the G357S mutation did not alter the Ca2+ activation of [3H]ryanodine binding or the Ca2+ induced release of Ca2+ from the intracellular stores in HEK293 cells. These data indicate that the CPVT-associated G357S mutation enhances the arrhythmogenic SOICR and reduces RyR2 protein expression, which may be attributable to the incomplete penetrance of CPVT in this family.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Mutação
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
Taquicardia Ventricular/genética
[Mh] Termos MeSH secundário: Western Blotting
Células HEK293
Seres Humanos
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Taquicardia Ventricular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ryanodine Receptor Calcium Release Channel); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184177


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[PMID]:28927399
[Au] Autor:Bánfai Z; Hadzsiev K; Pál E; Komlósi K; Melegh M; Balikó L; Melegh B
[Ad] Endereço:Department of Medical Genetics, University of Pécs, Szigeti út 12, Pécs, H-7624, Hungary.
[Ti] Título:Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.
[So] Source:BMC Med Genet;18(1):105, 2017 Sep 19.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. CASE PRESENTATION: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. CONCLUSIONS: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.
[Mh] Termos MeSH primário: Miosinas Cardíacas/genética
Variação Genética
Doenças Musculares/congênito
Cadeias Pesadas de Miosina/genética
[Mh] Termos MeSH secundário: Miopatias Distais/diagnóstico por imagem
Miopatias Distais/genética
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Músculo Esquelético/patologia
Doenças Musculares/diagnóstico por imagem
Doenças Musculares/genética
Mutação
Miopatias Congênitas Estruturais/diagnóstico por imagem
Miopatias Congênitas Estruturais/genética
Oftalmoplegia/diagnóstico por imagem
Oftalmoplegia/genética
Fenótipo
Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MYH7 protein, human); 0 (Ryanodine Receptor Calcium Release Channel); EC 3.6.1.- (Cardiac Myosins); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0463-y


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[PMID]:28916620
[Au] Autor:Hanna AD; Lam A; Thekkedam C; Willemse H; Dulhunty AF; Beard NA
[Ad] Endereço:John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia (A.D.H., A.L., C.T., A.F.D.) and Health Research Institute, Faculty of Education, Science, Technology and Maths, University of Canberra, Australian Capital Territory, Canberra, A
[Ti] Título:The Anthracycline Metabolite Doxorubicinol Abolishes RyR2 Sensitivity to Physiological Changes in Luminal Ca through an Interaction with Calsequestrin.
[So] Source:Mol Pharmacol;92(5):576-587, 2017 Nov.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The chemotherapeutic anthracycline metabolite doxorubicinol (doxOL) has been shown to interact with and disrupt the function of the cardiac ryanodine receptor Ca release channel (RyR2) in the sarcoplasmic reticulum (SR) membrane and the SR Ca binding protein calsequestrin 2 (CSQ2). Normal increases in RyR2 activity in response to increasing diastolic SR [Ca ] are influenced by CSQ2 and are disrupted in arrhythmic conditions. Therefore, we explored the action of doxOL on RyR2's response to changes in luminal [Ca ] seen during diastole. DoxOL abolished the increase in RyR2 activity when luminal Ca was increased from 0.1 to 1.5 mM. This was not due to RyR2 oxidation, but depended entirely on the presence of CSQ2 in the RyR2 complex. DoxOL binding to CSQ2 reduced both the Ca binding capacity of CSQ2 (by 48%-58%) and its aggregation, and lowered CSQ2 association with the RyR2 complex by 67%-77%. Each of these effects on CSQ2, and the lost RyR2 response to changes in luminal [Ca ], was duplicated by exposing native RyR2 channels to subphysiologic (≤1.0 µM) luminal [Ca ]. We suggest that doxOL and low luminal Ca both disrupt the CSQ2 polymer, and that the association of the monomeric protein with the RyR2 complex shifts the increase in RyR2 activity with increasing luminal [Ca ] away from the physiologic [Ca ] range. Subsequently, these changes may render the channel insensitive to changes of luminal Ca that occur through the cardiac cycle. The altered interactions between CSQ2, triadin, and/or junctin and RyR2 may produce an arrhythmogenic substrate in anthracycline-induced cardiotoxicity.
[Mh] Termos MeSH primário: Antraciclinas/metabolismo
Cálcio/metabolismo
Calsequestrina/metabolismo
Doxorrubicina/análogos & derivados
Miócitos Cardíacos/metabolismo
Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia
[Mh] Termos MeSH secundário: Animais
Antraciclinas/farmacologia
Cálcio/fisiologia
Sinalização do Cálcio/efeitos dos fármacos
Sinalização do Cálcio/fisiologia
Calsequestrina/farmacologia
Técnicas de Cultura de Células/métodos
Relação Dose-Resposta a Droga
Doxorrubicina/metabolismo
Doxorrubicina/farmacologia
Interações Medicamentosas/fisiologia
Miócitos Cardíacos/efeitos dos fármacos
Retículo Sarcoplasmático/efeitos dos fármacos
Retículo Sarcoplasmático/metabolismo
Ovinos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthracyclines); 0 (Calsequestrin); 0 (Ryanodine Receptor Calcium Release Channel); 80168379AG (Doxorubicin); HUH05KI4CF (adriamycinol); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1124/mol.117.108183


  9 / 5496 MEDLINE  
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[PMID]:28912111
[Au] Autor:Zuo Y; Wang H; Xu Y; Huang J; Wu S; Wu Y; Yang Y
[Ad] Endereço:College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China. Electronic address: zuoyayun0734@163.com.
[Ti] Título:CRISPR/Cas9 mediated G4946E substitution in the ryanodine receptor of Spodoptera exigua confers high levels of resistance to diamide insecticides.
[So] Source:Insect Biochem Mol Biol;89:79-85, 2017 Oct.
[Is] ISSN:1879-0240
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Diamide insecticides selectively activate insect ryanodine receptors (RyRs), inducing uncontrolled release of calcium ions, and causing muscle contraction, paralysis and eventually death. The RyR substitution associated with diamide resistance has been identified in three lepidopteran pests, Plutella xylostella, Tuta absoluta and Chilo suppressalis. Recently, the T. absoluta RyR mutation was knocked into the model insect Drosophila melanogaster by CRISPR/Cas9 mediated genome editing and provided in vivo functional confirmation for its role in diamide resistance. In the present study, we successfully introduced the RyR mutation with CRISPR/Cas9 technology into a lepidopteran pest of global importance, Spodoptera exigua. The genome-edited strain (named 4946E) homozygous for the SeRyR mutation exhibited 223-, 336- and >1000-fold resistance to chlorantraniliprole, cyantraniliprole and flubendiamide, respectively when compared to the wild type strain (WHS) of S. exigua. Reciprocal crossing experiments revealed that the target-site resistance in strain 4946E underlies an autosomal and almost recessive mode of inheritance for anthranilic diamides, whereas it was completely recessive for flubendiamide. Our results not only provided in vivo functional validation of the RyR mutation in conferring high levels of resistance to diamide insecticides for the first time in a controlled genetic background of a lepidopteran pest, but also revealed slight differences on the level of resistance between anthranilic diamides (chlorantraniliprole and cyantraniliprole) and flubendiamide conferred by the SeRyR mutation.
[Mh] Termos MeSH primário: Edição de Genes/métodos
Controle de Insetos/métodos
Resistência a Inseticidas/genética
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
Spodoptera/genética
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Sistemas CRISPR-Cas
Feminino
Inseticidas
Masculino
Mutação Puntual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insecticides); 0 (Ryanodine Receptor Calcium Release Channel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE


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[PMID]:28687594
[Au] Autor:Chen W; Koop A; Liu Y; Guo W; Wei J; Wang R; MacLennan DH; Dirksen RT; Chen SRW
[Ad] Endereço:Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
[Ti] Título:Reduced threshold for store overload-induced Ca release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease.
[So] Source:Biochem J;474(16):2749-2761, 2017 Aug 07.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and central core disease (CCD), whereas mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most disease-associated RyR1 and RyR2 mutations are located in the N-terminal, central, and C-terminal regions of the corresponding ryanodine receptor (RyR) isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca release during store Ca overload, a process known as store overload-induced Ca release (SOICR). Considering the similar locations of disease-associated RyR1 and RyR2 mutations in the RyR structure, we hypothesize that like CPVT-associated RyR2 mutations, MH/CCD-associated RyR1 mutations also enhance SOICR. To test this hypothesis, we determined the impact on SOICR of 12 MH/CCD-associated RyR1 mutations E2347-del, R2163H, G2434R, R2435L, R2435H, and R2454H located in the central region, and Y4796C, T4826I, L4838V, A4940T, G4943V, and P4973L located in the C-terminal region of the channel. We found that all these RyR1 mutations reduced the threshold for SOICR. Dantrolene, an acute treatment for MH, suppressed SOICR in HEK293 cells expressing the RyR1 mutants R164C, Y523S, R2136H, R2435H, and Y4796C. Interestingly, carvedilol, a commonly used ß-blocker that suppresses RyR2-mediated SOICR, also inhibits SOICR in these RyR1 mutant HEK293 cells. Therefore, these results indicate that a reduced SOICR threshold is a common defect of MH/CCD-associated RyR1 mutations, and that carvedilol, like dantrolene, can suppress RyR1-mediated SOICR. Clinical studies of the effectiveness of carvedilol as a long-term treatment for MH/CCD or other RyR1-associated disorders may be warranted.
[Mh] Termos MeSH primário: Sinalização do Cálcio
Hipertermia Maligna/genética
Modelos Moleculares
Miopatia da Parte Central/genética
Mutação Puntual
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/farmacologia
Substituição de Aminoácidos
Animais
Sinalização do Cálcio/efeitos dos fármacos
Carbazóis/farmacologia
Dantroleno/farmacologia
Transferência Ressonante de Energia de Fluorescência
Predisposição Genética para Doença
Células HEK293
Seres Humanos
Hipertermia Maligna/tratamento farmacológico
Hipertermia Maligna/metabolismo
Microscopia de Fluorescência
Relaxantes Musculares Centrais/farmacologia
Mutagênese Sítio-Dirigida
Miopatia da Parte Central/metabolismo
Propanolaminas/farmacologia
Conformação Proteica
Coelhos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Canal de Liberação de Cálcio do Receptor de Rianodina/química
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Análise de Célula Única
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Carbazoles); 0 (Muscle Relaxants, Central); 0 (Propanolamines); 0 (Recombinant Proteins); 0 (Ryanodine Receptor Calcium Release Channel); 0K47UL67F2 (carvedilol); F64QU97QCR (Dantrolene)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170282



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