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Pesquisa : D02.455.849.291.686 [Categoria DeCS]
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[PMID]:28584051
[Au] Autor:Mowrey DD; Xu L; Mei Y; Pasek DA; Meissner G; Dokholyan NV
[Ad] Endereço:From the Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7260.
[Ti] Título:Ion-pulling simulations provide insights into the mechanisms of channel opening of the skeletal muscle ryanodine receptor.
[So] Source:J Biol Chem;292(31):12947-12958, 2017 Aug 04.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The type 1 ryanodine receptor (RyR1) mediates Ca release from the sarcoplasmic reticulum to initiate skeletal muscle contraction and is associated with muscle diseases, malignant hyperthermia, and central core disease. To better understand RyR1 channel function, we investigated the molecular mechanisms of channel gating and ion permeation. An adequate model of channel gating requires accurate, high-resolution models of both open and closed states of the channel. To this end, we generated an open-channel RyR1 model using molecular simulations to pull Ca through the pore constriction site of a closed-channel RyR1 structure determined at 3.8-Šresolution. Importantly, we find that our open-channel model is consistent with the RyR1 and cardiac RyR (RyR2) open-channel structures reported while this paper was in preparation. Both our model and the published structures show similar rotation of the upper portion of the pore-lining S6 helix away from the 4-fold channel axis and twisting of Ile-4937 at the channel constriction site out of the channel pore. These motions result in a minimum open-channel pore radius of ∼3 Šformed by Gln-4933, rather than Ile-4937 in the closed-channel structure. We also present functional support for our model by mutations around the closed- and open-channel constriction sites (Gln-4933 and Ile-4937). Our results indicate that use of ion-pulling simulations produces a RyR1 open-channel model, which can provide insights into the mechanisms of channel opening complementing those from the structural data.
[Mh] Termos MeSH primário: Sinalização do Cálcio
Bicamadas Lipídicas/química
Modelos Moleculares
Canal de Liberação de Cálcio do Receptor de Rianodina/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Cafeína/química
Cafeína/metabolismo
Cafeína/farmacologia
Agonistas dos Canais de Cálcio/química
Agonistas dos Canais de Cálcio/metabolismo
Agonistas dos Canais de Cálcio/farmacologia
Sinalização do Cálcio/efeitos dos fármacos
Glutamina/química
Células HEK293
Seres Humanos
Isoleucina/química
Ligantes
Simulação de Dinâmica Molecular
Mutação
Fragmentos de Peptídeos/agonistas
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Conformação Proteica em alfa-Hélice
Domínios e Motivos de Interação entre Proteínas
Coelhos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Rianodina/química
Rianodina/metabolismo
Rianodina/farmacologia
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Agonists); 0 (Ligands); 0 (Lipid Bilayers); 0 (Peptide Fragments); 0 (Recombinant Proteins); 0 (Ryanodine Receptor Calcium Release Channel); 04Y7590D77 (Isoleucine); 0RH81L854J (Glutamine); 15662-33-6 (Ryanodine); 3G6A5W338E (Caffeine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.760199


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[PMID]:28445755
[Au] Autor:Ngo VA; Perissinotti LL; Miranda W; Chen SRW; Noskov SY
[Ad] Endereço:Center for Molecular Simulations, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
[Ti] Título:Mapping Ryanodine Binding Sites in the Pore Cavity of Ryanodine Receptors.
[So] Source:Biophys J;112(8):1645-1653, 2017 Apr 25.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ryanodine (Ryd) irreversibly targets ryanodine receptors (RyRs), a family of intracellular calcium release channels essential for many cellular processes ranging from muscle contraction to learning and memory. Little is known of the atomistic details about how Ryd binds to RyRs. In this study, we used all-atom molecular dynamics simulations with both enhanced and bidirectional sampling to gain direct insights into how Ryd interacts with major residues in RyRs that were experimentally determined to be critical for its binding. We found that the pyrrolic ring of Ryd displays preference for the R AGGG-F residues in the cavity of RyR1, which explain the effects of the corresponding mutations in RyR2 in experiments. Particularly, the mutant Q4933A (or Q4863A in RyR2) critical for both the gating and Ryd binding not only has significantly less interaction with Ryd than the wild-type, but also yields more space for Ryd and water molecules in the cavity. These results describe clear binding modes of Ryd in the RyR cavity and offer structural mechanisms explaining functional data collected on RyR blockade.
[Mh] Termos MeSH primário: Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Rianodina/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Mutação
Estrutura Secundária de Proteína
Rianodina/química
Canal de Liberação de Cálcio do Receptor de Rianodina/química
Canal de Liberação de Cálcio do Receptor de Rianodina/genética
Termodinâmica
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ryanodine Receptor Calcium Release Channel); 059QF0KO0R (Water); 15662-33-6 (Ryanodine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE


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[PMID]:28159581
[Au] Autor:Vargas-Jaimes L; Xiao L; Zhang J; Possani LD; Valdivia HH; Quintero-Hernández V
[Ad] Endereço:Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62271, México.
[Ti] Título:Recombinant expression of Intrepicalcin from the scorpion Vaejovis intrepidus and its effect on skeletal ryanodine receptors.
[So] Source:Biochim Biophys Acta;1861(4):936-946, 2017 04.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Scorpion venoms contain toxins that modulate ionic channels, among which are the calcins, a small group of short, basic peptides with an Inhibitor Cystine Knot (ICK) motif that target calcium release channels/ryanodine receptors (RyRs) with high affinity and selectivity. Here we describe the heterologous expression of Intrepicalcin, identified by transcriptomic analysis of venomous glands from Vaejovis intrepidus. METHODS: Recombinant Intrepicalcin was obtained in Escherichia coli BL21-DE3 (periplasm) by fusing the Intrepicalcin gene to sequences coding for signal-peptide, thioredoxin, His-tag and enterokinase cleavage site. RESULTS: [ H]Ryanodine binding, used as a functional index of RyR activity, revealed that recombinant Intrepicalcin activates skeletal RyR (RyR1) dose-dependently with K =17.4±4.0nM. Intrepicalcin significantly augments the bell-shaped [Ca ]-[ H]ryanodine binding curve at all [Ca ] ranges, as is characteristic of the calcins. In single channel recordings, Intrepicalcin induces the appearance of a subconductance state in RyR1 with a fractional value ∼55% of the full conductance state, very close to that of Vejocalcin. Furthermore, Intrepicalcin stimulates Ca release at an initial dose=45.3±2.5nM, and depletes ~50% of Ca load from skeletal sarcoplasmic reticulum vesicles. CONCLUSIONS: We conclude that active recombinant Intrepicalcin was successfully obtained without the need of manual oxidation, enabling it to target RyR1s with high affinity. GENERAL SIGNIFICANCE: This is the first calcin heterologously expressed in the periplasma of Escherichia coli BL21-DE3, shown to be pharmacologically effective, thus paving the way for the generation of Intrepicalcin variants that are required for structure-function relationship studies of calcins and RyRs.
[Mh] Termos MeSH primário: Músculo Esquelético/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Venenos de Escorpião/genética
Venenos de Escorpião/metabolismo
Escorpiões/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sequência de Bases
Cálcio/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Modelos Moleculares
Peptídeos/genética
Peptídeos/metabolismo
Coelhos
Ratos
Rianodina/metabolismo
Retículo Sarcoplasmático/metabolismo
Escorpiões/genética
Tiorredoxinas/metabolismo
Transcriptoma/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 (Peptides); 0 (Recombinant Proteins); 0 (Ryanodine Receptor Calcium Release Channel); 0 (Scorpion Venoms); 15662-33-6 (Ryanodine); 52500-60-4 (Thioredoxins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE
[do] DOI:10.1016/j.bbagen.2017.01.032


  4 / 2800 MEDLINE  
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[PMID]:28143888
[Au] Autor:Zhang R; Pessah IN
[Ad] Endereço:Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis (R.Z., I.N.P.), and The Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento (I.N.P.), California ruizhang@ucdavis.edu.
[Ti] Título:Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A.
[So] Source:Mol Pharmacol;91(4):428-436, 2017 Apr.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bisphenol A (BPA) and its brominated derivative tetrabromobisphenol A (TBBPA) are high production volume chemicals used in the manufacture of various consumer products. Although regarded as endocrine disruptors, these chemicals are suspected to exert nongenomic actions on muscle function that are not well understood. Using skeletal muscle microsomes, we examined the effects of BPA and TBBPA on ryanodine receptor type 1 (RyR1), dihydropyridine receptor (DHPR), and sarcoplasmic/endoplasmic reticulum Ca ATPase (SERCA). We assessed the impact of these chemicals on Ca dynamics and signaling in embryonic skeletal myotubes through fluorescent Ca imaging and measurement of resting membrane potential ( ). TBBPA activated RyR1 and inhibited DHPR and SERCA, inducing a net efflux of Ca from loaded microsomes, whereas BPA exhibited little or no activity at these targets. Regardless, both compounds disrupted the function of intact myotubes. TBBPA diminished and eventually abrogated Ca transients, altered intracellular Ca equilibrium, and caused depolarization. For some cells, BPA caused rapid Ca transient loss without marked changes in cytosolic and sarcoplasmic reticulum Ca levels, likely owing to altered cellular excitability as a result of BPA-induced hyperpolarization. BPA and TBBPA both interfere with skeletal muscle function through divergent mechanisms that impair excitation-contraction coupling and may be exemplary of their adverse outcomes in other muscle types.
[Mh] Termos MeSH primário: Compostos Benzidrílicos/farmacologia
Músculo Esquelético/embriologia
Músculo Esquelético/metabolismo
Fenóis/farmacologia
Bifenil Polibromatos/farmacologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Acoplamento Excitação-Contração/efeitos dos fármacos
Fluorescência
Homeostase/efeitos dos fármacos
Masculino
Camundongos
Microssomos/efeitos dos fármacos
Microssomos/metabolismo
Modelos Biológicos
Fibras Musculares Esqueléticas/efeitos dos fármacos
Fibras Musculares Esqueléticas/metabolismo
Músculo Esquelético/efeitos dos fármacos
Coelhos
Ensaio Radioligante
Rianodina/metabolismo
Triclosan/farmacologia
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzhydryl Compounds); 0 (Phenols); 0 (Polybrominated Biphenyls); 10028-17-8 (Tritium); 15662-33-6 (Ryanodine); 4NM5039Y5X (Triclosan); FQI02RFC3A (tetrabromobisphenol A); MLT3645I99 (bisphenol A); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.1124/mol.116.107342


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[PMID]:28130256
[Au] Autor:Mukherjee S; Sheng W; Sun R; Janssen LJ
[Ad] Endereço:Firestone Institute for Respiratory Health, St. Joseph's Hospital, Department of Medicine, McMaster University, Hamilton, Ontario, Canada smukher@mcmaster.ca subh812002@gmail.com.
[Ti] Título:Ca /calmodulin-dependent protein kinase IIß and IIδ mediate TGFß-induced transduction of fibronectin and collagen in human pulmonary fibroblasts.
[So] Source:Am J Physiol Lung Cell Mol Physiol;312(4):L510-L519, 2017 Apr 01.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is now clear that in addition to activating several complex kinase pathways (Smad, MAP kinase, PI3 kinase), TGFß also acts by elevating cytosolic Ca concentration within human pulmonary fibroblasts. Ca /calmodulin-dependent protein kinase II (CamK II) is also known to regulate gene expression in fibroblasts. In this study, we examined the interactions between calcium signaling, activation of CamK and other kinases, and extracellular matrix (ECM) gene expression. Human pulmonary fibroblasts were cultured and stimulated with artificially generated Ca pulses in the absence of TGFß, or with TGFß (1 nM) or vehicle in the presence of various blockers of Ca signaling. PCR and Western blotting were used to measure gene expression and protein levels, respectively. We found that Ca pulses in the absence of TGFß increased ECM gene expression in a pulse frequency-dependent manner, and that blocking Ca signaling and the CamK II pathway significantly reduced TGFß-mediated ECM gene expression, without having any effects on other kinase pathways (Smad, PI3 kinase, or MAP kinase). We also found that TGFß elevated the expression of CamK IIß and CamK IIδ, while siRNA silencing of those two subtypes significantly reduced TGFß-mediated expression of collagen A1 and fibronectin 1. Our data suggest that TGFß induces the expression of CamK IIß and CamK IIδ, which in turn are activated by TGFß-evoked Ca waves in a frequency-dependent manner, leading to increased expression of ECM proteins.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Colágeno Tipo I/metabolismo
Fibroblastos/metabolismo
Fibronectinas/metabolismo
Pulmão/citologia
Transdução de Sinais/efeitos dos fármacos
Fator de Crescimento Transformador beta/farmacologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Western Blotting
Sinalização do Cálcio
Proteínas da Matriz Extracelular/genética
Proteínas da Matriz Extracelular/metabolismo
Fibroblastos/efeitos dos fármacos
Regulação da Expressão Gênica
Seres Humanos
Indóis/farmacologia
Isoenzimas/genética
Isoenzimas/metabolismo
Masculino
Meia-Idade
Fosforilação/efeitos dos fármacos
Rianodina/farmacologia
Transdução de Sinais/genética
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Collagen Type I); 0 (Extracellular Matrix Proteins); 0 (Fibronectins); 0 (Indoles); 0 (Isoenzymes); 0 (Transforming Growth Factor beta); 0 (collagen type I, alpha 1 chain); 15662-33-6 (Ryanodine); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); X9TLY4580Z (cyclopiazonic acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170612
[Lr] Data última revisão:
170612
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170129
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00084.2016


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[PMID]:28115480
[Au] Autor:Khomula EV; Ferrari LF; Araldi D; Levine JD
[Ad] Endereço:Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143.
[Ti] Título:Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP Receptors in the Induction of Hyperalgesic Priming.
[So] Source:J Neurosci;37(8):2032-2044, 2017 Feb 22.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP ) receptor inhibitor prevented the induction of priming by ryanodine. For IP induced priming, females were also more sensitive. IP -induced priming was prevented by pretreatment with inhibitors of the sarcoendoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low-dose IP in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP antagonist. Thus, an EsRα-dependent bidirectional interaction between endoplasmic reticulum IP and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male DRG neurons, IP (100 µm) potentiated depolarization-induced transients produced by extracellular application of high-potassium solution (20 mm, K20), in nociceptors incubated with ß-estradiol. This potentiation of depolarization-induced calcium transients was blocked by the IP antagonist, and not observed in the absence of IP IP potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nm), instead of IP , also potentiated K20-induced calcium transients in the presence of ß-estradiol, in an IP receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP and ryanodine receptors that contributes to sex differences in hyperalgesic priming. The present study demonstrates a mechanism that plays a role in the marked sexual dimorphism observed in a model of the transition to chronic pain, hyperalgesic priming. This mechanism involves a reciprocal interaction between the endoplasmic reticulum receptors, IP and ryanodine, in the induction of priming, regulated by estrogen receptor α in the nociceptor of female rats. The presence of this signaling pathway modulating the susceptibility of nociceptors to develop plasticity may contribute to our understanding of sex differences observed clinically in chronic pain syndromes.
[Mh] Termos MeSH primário: Hiperalgesia/metabolismo
Receptores de Inositol 1,4,5-Trifosfato/metabolismo
Limiar da Dor/fisiologia
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
Caracteres Sexuais
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Dinoprostona/efeitos adversos
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
Feminino
Gânglios Espinais/citologia
Hiperalgesia/induzido quimicamente
Inositol 1,4,5-Trifosfato/farmacologia
Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores
Compostos Macrocíclicos/farmacologia
Masculino
Oligodesoxirribonucleotídeos Antissenso/farmacologia
Oxazóis/farmacologia
Medição da Dor
Limiar da Dor/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Rianodina/efeitos adversos
Células Receptoras Sensoriais/efeitos dos fármacos
Tapsigargina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (Macrocyclic Compounds); 0 (Oligodeoxyribonucleotides, Antisense); 0 (Oxazoles); 0 (Ryanodine Receptor Calcium Release Channel); 0 (xestospongin C); 15662-33-6 (Ryanodine); 67526-95-8 (Thapsigargin); 85166-31-0 (Inositol 1,4,5-Trisphosphate); K7Q1JQR04M (Dinoprostone)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2911-16.2017


  7 / 2800 MEDLINE  
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[PMID]:28087340
[Au] Autor:Tuncer S; Dalkilic N; Burat I
[Ad] Endereço:NEU Meram Medical Faculty, Department of Biophysics, Konya, Turkey. Electronic address: tuncerseckin@gmail.com.
[Ti] Título:Electrophysiological alterations in diaphragm muscle caused by abdominal ischemia-reperfusion.
[So] Source:Respir Physiol Neurobiol;238:7-13, 2017 Apr.
[Is] ISSN:1878-1519
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Ischemia-reperfusion injury is the major complication of abdominal aortic surgery, and it mainly affects the lower extremities and remote organs. In the present study, the electrophysiological alterations in diaphragm that underlie the post-operative respiratory dysfunction were investigated. Wistar Albino rats were randomly divided into two groups: SHAM (only laparotomy was performed) and IR (abdominal aorta was clamped for 30min and reperfused for 2h). Following the operational period diaphragm muscles were isolated and electrophysiological experiments were carried out in-vitro. 3nM Ryanodine application, Na and K current blockage (0.3mM 4-Aminopyridine and 127mM N-methyl-d-glukamine) experiments were also conducted to further reveal any alterations. Twitch and tetanic force were decreased significantly. Action potential overshoot, amplitude and area were increased while diaphragm muscle cells were found to be hyperpolarized significantly. Mechanical alterations were shown to be caused by deterioration of Ca homeostasis. At resting state, a decrease in persistent Na current was found. The reshaping of action potential, on the other hand, was shown to be due to altered kinetics of Na channels and delayed activation of voltage dependent K channels.
[Mh] Termos MeSH primário: Potenciais de Ação/fisiologia
Diafragma/fisiopatologia
Isquemia/patologia
Contração Muscular/fisiologia
Traumatismo por Reperfusão/patologia
[Mh] Termos MeSH secundário: 4-Aminopiridina/farmacologia
Potenciais de Ação/efeitos dos fármacos
Análise de Variância
Animais
Biofísica
Diafragma/efeitos dos fármacos
Modelos Animais de Doenças
Estimulação Elétrica
Agonistas de Aminoácidos Excitatórios/farmacologia
Masculino
N-Metilaspartato/farmacologia
Bloqueadores dos Canais de Potássio/farmacologia
Ratos
Ratos Wistar
Rianodina/farmacologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Agonists); 0 (Potassium Channel Blockers); 15662-33-6 (Ryanodine); 6384-92-5 (N-Methylaspartate); BH3B64OKL9 (4-Aminopyridine)
[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:170115
[St] Status:MEDLINE


  8 / 2800 MEDLINE  
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[PMID]:28052355
[Au] Autor:Kupynyak NI; Ikkert OV; Shlykov SG; Babich LG; Manko VV
[Ad] Endereço:Ivan Franko National University of Lviv, Lviv, Ukraine.
[Ti] Título:Mitochondrial ryanodine-sensitive Ca channels of rat liver.
[So] Source:Cell Biochem Funct;35(1):42-49, 2017 Jan.
[Is] ISSN:1099-0844
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To examine ryanodine-sensitive Ca channels in mitochondria of rat hepatocytes and their role in energy state of the cells via investigation of the ryanodine effect on mitochondrial membrane potential. Oxygen consumption was measured by polarography using the Clark electrode. The substrates of oxidation such as pyruvate (5mM), α-ketoglutarate (5mM), or succinate (5mM) were used. Oxidative phosphorylation was stimulated by the addition of adenosine diphosphate (200nM). Mitochondrial membrane potential was measured using a voltage-sensitive fluorescent probe tetramethylrhodamine-methyl-ester (0.1µM) and was analyzed by a flow cytometer. To evaluate the intact mitochondria, we used carbonil cyanide m-chlorophenyl hydrazone (CCCP, 10µM). Changes in the ionized calcium concentration in rat liver mitochondria were measured using a fluorescent probe Fluo-4 AM. Effect of ryanodine on oxygen consumption of rat liver mitochondria depends on the oxidation substrate and the incubation time. Oxidation of pyruvate in the presence of ryanodine (0.05µM) decreased the membrane potential of rat liver mitochondria by 38.4%. At higher concentrations, ryanodine (0.1µM or 1µM) led to decrease of membrane potential by 51.7% and 42.8%, respectively. In contrast, oxidation of α-ketoglutarate in the presence of ryanodine (0.05µM) increased mitochondrial membrane potential by 16.8%. However, at higher concentrations, ryanodine (0.1µM or 1µM) triggered a decreasing of membrane potential by 42.5% and 31.0%, respectively. Therefore, ryanodine at various concentrations (0.05µM, 0.1µM, or 1µM) causes differential effects on Ca concentration in the mitochondria matrix under oxidation of pyruvate or α-ketoglutarate. The data suggest the presence of ryanodine receptors in mitochondrial membrane of rat hepatocytes. Their inhibition with higher concentrations of ryanodine leads to decreasing of intra-mitochondrial Ca concentration and affecting the energy state of mictochondria in hepatocytes.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
Fígado/metabolismo
Mitocôndrias Hepáticas/efeitos dos fármacos
Rianodina/farmacologia
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Ácidos Cetoglutáricos/química
Ácidos Cetoglutáricos/metabolismo
Masculino
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias Hepáticas/metabolismo
Oxirredução
Consumo de Oxigênio/efeitos dos fármacos
Ácido Pirúvico/química
Ácido Pirúvico/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels); 0 (Ketoglutaric Acids); 15662-33-6 (Ryanodine); 8558G7RUTR (Pyruvic Acid); 8ID597Z82X (alpha-ketoglutaric acid); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170125
[Lr] Data última revisão:
170125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170105
[St] Status:MEDLINE
[do] DOI:10.1002/cbf.3243


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[PMID]:27866274
[Au] Autor:Matsuki K; Takemoto M; Suzuki Y; Yamamura H; Ohya S; Takeshima H; Imaizumi Y
[Ad] Endereço:Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
[Ti] Título:Ryanodine receptor type 3 does not contribute to contractions in the mouse myometrium regardless of pregnancy.
[So] Source:Pflugers Arch;469(2):313-326, 2017 Feb.
[Is] ISSN:1432-2013
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Ryanodine receptor type 3 (RyR3) is expressed in myometrial smooth muscle cells (MSMCs). The short isoform of RyR3 is a dominant negative variant (DN-RyR3) and negatively regulates the functions of RyR2 and full-length (FL)-RyR3. DN-RyR3 has been suggested to function as a major RyR3 isoform in non-pregnant (NP) mouse MSMCs, and FL-RyR3 may also be upregulated during pregnancy (P). This increase in the FL-RyR3/DN-RyR3 ratio may contribute to the strong contractions by MSMCs for parturition. In the present study, spontaneous contractions by the myometrium in NP and P mice were highly susceptible to nifedipine but were not affected by ryanodine. Ca image analyses under a voltage clamp revealed that the influx of Ca through voltage-dependent Ca channels did not cause the release of Ca from the sarcoplasmic reticulum (SR). Cytosolic Ca concentrations ([Ca ] ) in MSMCs were not affected by caffeine. Despite the abundant expression of large conductance Ca -activated K channels in MSMCs, spontaneous transient outward currents were not observed in the resting state because of the substantive lack of Ca sparks. Quantitative PCR and Western blot analyses indicated that DN-RyR3 was strongly expressed in the NP myometrium, while the expression of FL-RyR3 and DN-RyR3 was markedly reduced in the P myometrium. The messenger RNA (mRNA) expression of RyR2 and RyR1 was negligible in the NP and P myometria. Moreover, RyR3 knockout mice may become pregnant and deliver normally. Thus, we concluded that none of the RyR subtypes, including RyR3, play a significant role in the regulation of [Ca ] in or contractions by mouse MSMCs regardless of pregnancy.
[Mh] Termos MeSH primário: Contração Muscular/fisiologia
Miométrio/metabolismo
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
[Mh] Termos MeSH secundário: Animais
Cafeína/farmacologia
Cálcio/metabolismo
Sinalização do Cálcio/efeitos dos fármacos
Sinalização do Cálcio/fisiologia
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/metabolismo
Miométrio/efeitos dos fármacos
Potássio/metabolismo
Gravidez
Isoformas de Proteínas/metabolismo
RNA Mensageiro/metabolismo
Rianodina/metabolismo
Retículo Sarcoplasmático/efeitos dos fármacos
Retículo Sarcoplasmático/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Isoforms); 0 (RNA, Messenger); 0 (Ryanodine Receptor Calcium Release Channel); 15662-33-6 (Ryanodine); 3G6A5W338E (Caffeine); RWP5GA015D (Potassium); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161121
[St] Status:MEDLINE
[do] DOI:10.1007/s00424-016-1900-z


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[PMID]:27926840
[Au] Autor:Her C; McCaffrey JE; Thomas DD; Karim CB
[Ad] Endereço:Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
[Ti] Título:Calcium-Dependent Structural Dynamics of a Spin-Labeled RyR Peptide Bound to Calmodulin.
[So] Source:Biophys J;111(11):2387-2394, 2016 Dec 06.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have used chemical synthesis, electron paramagnetic resonance (EPR), and circular dichroism to detect and analyze the structural dynamics of a ryanodine receptor (RyR) peptide bound to calmodulin (CaM). The skeletal muscle calcium release channel RyR1 is activated by Ca -free CaM and inhibited by Ca -bound CaM. To probe the structural mechanism for this regulation, wild-type RyRp and four spin-labeled derivatives were synthesized, each containing the nitroxide probe 2,2,6,6-tetramethyl-piperidine-1-oxyl-4-amino-4-carboxylic acid substituted for a single amino acid. In 2,2,6,6-tetramethyl-piperidine-1-oxyl-4-amino-4-carboxylic acid, the probe is rigidly and stereospecifically coupled to the α-carbon, enabling direct detection by EPR of peptide backbone structural dynamics. In the absence of CaM, circular dichroism indicates a complete lack of secondary structure, while 40% trifluoroethanol (TFE) induces >90% helicity and is unperturbed by the spin label. The EPR spectrum of each spin-labeled peptide indicates nanosecond dynamic disorder that is substantially reduced by TFE, but a significant gradient in dynamics is observed, decreasing from N- to C-terminus, both in the presence and absence of TFE. When bound to CaM, the probe nearest RyRp's N-terminus shows rapid rotational motion consistent with peptide backbone dynamics of a locally unfolded peptide, while the other three sites show substantial restriction of dynamics, consistent with helical folding. The two N-terminal sites, which bind to the C-lobe of CaM, do not show a significant Ca -dependence in mobility, while both C-terminal sites, which bind to the N-lobe of CaM, are significantly less mobile in the presence of bound Ca . These results support a model in which the interaction of RyR with CaM is nonuniform along the peptide, and the primary effect of Ca is to increase the interaction of the C-terminal portion of the peptide with the N-terminal lobe of CaM. These results provide, to our knowledge, new insight into the Ca -dependent regulation of RyR by CaM.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Calmodulina/metabolismo
Rianodina/química
Rianodina/metabolismo
Marcadores de Spin
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Óxidos N-Cíclicos/química
Modelos Moleculares
Ligação Proteica
Conformação Proteica em alfa-Hélice
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calmodulin); 0 (Cyclic N-Oxides); 0 (Spin Labels); 15662-33-6 (Ryanodine); SY7Q814VUP (Calcium); XDN8H1XM17 (2,2,6,6-tetramethylpiperidine-N-oxide-4-amino-4-carboxylic acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161208
[St] Status:MEDLINE



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