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[PMID]:29348575
[Au] Autor:Neef J; Urban NT; Ohn TL; Frank T; Jean P; Hell SW; Willig KI; Moser T
[Ad] Endereço:Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099, Göttingen, Germany.
[Ti] Título:Quantitative optical nanophysiology of Ca signaling at inner hair cell active zones.
[So] Source:Nat Commun;9(1):290, 2018 01 18.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ca influx triggers the release of synaptic vesicles at the presynaptic active zone (AZ). A quantitative characterization of presynaptic Ca signaling is critical for understanding synaptic transmission. However, this has remained challenging to establish at the required resolution. Here, we employ confocal and stimulated emission depletion (STED) microscopy to quantify the number (20-330) and arrangement (mostly linear 70 nm × 100-600 nm clusters) of Ca channels at AZs of mouse cochlear inner hair cells (IHCs). Establishing STED Ca imaging, we analyze presynaptic Ca signals at the nanometer scale and find confined elongated Ca domains at normal IHC AZs, whereas Ca domains are spatially spread out at the AZs of bassoon-deficient IHCs. Performing 2D-STED fluorescence lifetime analysis, we arrive at estimates of the Ca concentrations at stimulated IHC AZs of on average 25 µM. We propose that IHCs form bassoon-dependent presynaptic Ca -channel clusters of similar density but scalable length, thereby varying the number of Ca channels amongst individual AZs.
[Mh] Termos MeSH primário: Sinalização do Cálcio/fisiologia
Células Ciliadas Auditivas Internas/fisiologia
Microscopia/métodos
Nanotecnologia/métodos
[Mh] Termos MeSH secundário: Algoritmos
Animais
Cálcio/metabolismo
Canais de Cálcio Tipo L/fisiologia
Células Ciliadas Auditivas Internas/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microscopia Confocal
Modelos Neurológicos
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/fisiologia
Sinapses/metabolismo
Sinapses/fisiologia
Transmissão Sináptica/genética
Transmissão Sináptica/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bsn protein, mouse); 0 (Calcium Channels, L-Type); 0 (Nerve Tissue Proteins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02612-y


  2 / 6897 MEDLINE  
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[PMID]:29348113
[Au] Autor:Monticone S; Buffolo F; Tetti M; Veglio F; Pasini B; Mulatero P
[Ad] Endereço:Division of Internal Medicine and Hypertension UnitDepartment of Medical Sciences, University of Torino, Torino, Italy.
[Ti] Título:GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism.
[So] Source:Eur J Endocrinol;178(3):R101-R111, 2018 Mar.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes ( and ), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in and cause FH-III and FH-IV, respectively, while germline mutations in cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/genética
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética
Hiperaldosteronismo/genética
ATPases Transportadoras de Cálcio da Membrana Plasmática/genética
ATPase Trocadora de Sódio-Potássio/genética
[Mh] Termos MeSH secundário: Aldosterona/biossíntese
Variação Genética
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (CACNA1D protein, human); 0 (Calcium Channels, L-Type); 0 (G Protein-Coupled Inwardly-Rectifying Potassium Channels); 0 (KCNJ5 protein, human); 4964P6T9RB (Aldosterone); EC 3.6.1.- (ATP1A1 protein, human); EC 3.6.3.8 (ATP2B3 protein, human); EC 3.6.3.8 (Plasma Membrane Calcium-Transporting ATPases); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-17-0946


  3 / 6897 MEDLINE  
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[PMID]:29288765
[Au] Autor:Kumari N; Gaur H; Bhargava A
[Ad] Endereço:Ion Channel Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Telangana 502285, India.
[Ti] Título:Cardiac voltage gated calcium channels and their regulation by ß-adrenergic signaling.
[So] Source:Life Sci;194:139-149, 2018 Feb 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Voltage-gated calcium channels (VGCCs) are the predominant source of calcium influx in the heart leading to calcium-induced calcium release and ultimately excitation-contraction coupling. In the heart, VGCCs are modulated by the ß-adrenergic signaling. Signaling through ß-adrenergic receptors (ßARs) and modulation of VGCCs by ß-adrenergic signaling in the heart are critical signaling and changes to these have been significantly implicated in heart failure. However, data related to calcium channel dysfunction in heart failure is divergent and contradictory ranging from reduced function to no change in the calcium current. Many recent studies have highlighted the importance of functional and spatial microdomains in the heart and that may be the key to answer several puzzling questions. In this review, we have briefly discussed the types of VGCCs found in heart tissues, their structure, and significance in the normal and pathological condition of the heart. More importantly, we have reviewed the modulation of VGCCs by ßARs in normal and pathological conditions incorporating functional and structural aspects. There are different types of ßARs, each having their own significance in the functioning of the heart. Finally, we emphasize the importance of location of proteins as it relates to their function and modulation by co-signaling molecules. Its implication on the studies of heart failure is speculated.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/metabolismo
Insuficiência Cardíaca/patologia
Miocárdio/patologia
Receptores Adrenérgicos beta/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Cálcio/metabolismo
Canais de Cálcio Tipo L/análise
Insuficiência Cardíaca/metabolismo
Seres Humanos
Miocárdio/metabolismo
Receptores Adrenérgicos beta/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (Receptors, Adrenergic, beta); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE


  4 / 6897 MEDLINE  
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[PMID]:29183797
[Au] Autor:Rodrigues AL; Brescia M; Koschinski A; Moreira TH; Cameron RT; Baillie G; Beirão PSL; Zaccolo M; Cruz JS
[Ad] Endereço:Laboratório CaCIA, Faculdade de Ciências Humanas Sociais e da Saúde, Universidade FUMEC, Brazil. Electronic address: alaura@fumec.br.
[Ti] Título:Increase in Ca current by sustained cAMP levels enhances proliferation rate in GH3 cells.
[So] Source:Life Sci;192:144-150, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Ca and cAMP are important intracellular modulators. In order to generate intracellular signals with various amplitudes, as well as different temporal and spatial properties, a tightly and precise control of these modulators in intracellular compartments is necessary. The aim of this study was to evaluate the effects of elevated and sustained cAMP levels on voltage-dependent Ca currents and proliferation in pituitary tumor GH3 cells. MAIN METHODS: Effect of long-term exposure to forskolin and dibutyryl-cyclic AMP (dbcAMP) on Ca current density and cell proliferation rate were determined by using the whole-cell patch-clamp technique and real time cell monitoring system. The cAMP levels were assayed, after exposing transfected GH3 cells with the EPAC-1 cAMP sensor to forskolin and dbcAMP, by FRET analysis. KEY FINDINGS: Sustained forskolin treatment (24 and 48h) induced a significant increase in total Ca current density in GH3 cells. Accordingly, dibutyryl-cAMP incubation (dbcAMP) also elicited increase in Ca current density. However, the maximum effect of dbcAMP occurred only after 72h incubation, whereas forskolin showed maximal effect at 48h. FRET-experiments confirmed that the time-course to elevate intracellular cAMP was distinct between forskolin and dbcAMP. Mibefradil inhibited the fast inactivating current component selectively, indicating the recruitment of T-type Ca channels. A significant increase on cell proliferation rate, which could be related to the elevated and sustained intracellular levels of cAMP was observed. SIGNIFICANCE: We conclude that maintaining high levels of intracellular cAMP will cause an increase in Ca current density and this phenomenon impacts proliferation rate in GH3 cells.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
AMP Cíclico/metabolismo
[Mh] Termos MeSH secundário: Animais
Bucladesina/farmacologia
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo L/efeitos dos fármacos
Canais de Cálcio Tipo T/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colforsina/farmacologia
Mibefradil/farmacologia
Técnicas de Patch-Clamp
Neoplasias Hipofisárias/metabolismo
Ratos
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels); 0 (Calcium Channels, L-Type); 0 (Calcium Channels, T-Type); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); 27B90X776A (Mibefradil); 63X7MBT2LQ (Bucladesine); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE


  5 / 6897 MEDLINE  
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[PMID]:29216239
[Au] Autor:Van Nieuwenhuyse E; Seemann G; Panfilov AV; Vandersickel N
[Ad] Endereço:Department of Physics and Astronomy, Ghent University, Ghent, Belgium.
[Ti] Título:Effects of early afterdepolarizations on excitation patterns in an accurate model of the human ventricles.
[So] Source:PLoS One;12(12):e0188867, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Early Afterdepolarizations, EADs, are defined as the reversal of the action potential before completion of the repolarization phase, which can result in ectopic beats. However, the series of mechanisms of EADs leading to these ectopic beats and related cardiac arrhythmias are not well understood. Therefore, we aimed to investigate the influence of this single cell behavior on the whole heart level. For this study we used a modified version of the Ten Tusscher-Panfilov model of human ventricular cells (TP06) which we implemented in a 3D ventricle model including realistic fiber orientations. To increase the likelihood of EAD formation at the single cell level, we reduced the repolarization reserve (RR) by reducing the rapid delayed rectifier Potassium current and raising the L-type Calcium current. Varying these parameters defined a 2D parametric space where different excitation patterns could be classified. Depending on the initial conditions, by either exciting the ventricles with a spiral formation or burst pacing protocol, we found multiple different spatio-temporal excitation patterns. The spiral formation protocol resulted in the categorization of a stable spiral (S), a meandering spiral (MS), a spiral break-up regime (SB), spiral fibrillation type B (B), spiral fibrillation type A (A) and an oscillatory excitation type (O). The last three patterns are a 3D generalization of previously found patterns in 2D. First, the spiral fibrillation type B showed waves determined by a chaotic bi-excitable regime, i.e. mediated by both Sodium and Calcium waves at the same time and in same tissue settings. In the parameter region governed by the B pattern, single cells were able to repolarize completely and different (spiral) waves chaotically burst into each other without finishing a 360 degree rotation. Second, spiral fibrillation type A patterns consisted of multiple small rotating spirals. Single cells failed to repolarize to the resting membrane potential hence prohibiting the Sodium channel gates to recover. Accordingly, we found that Calcium waves mediated these patterns. Third, a further reduction of the RR resulted in a more exotic parameter regime whereby the individual cells behaved independently as oscillators. The patterns arose due to a phase-shift of different oscillators as disconnection of the cells resulted in continuation of the patterns. For all patterns, we computed realistic 9 lead ECGs by including a torso model. The B and A type pattern exposed the behavior of Ventricular Tachycardia (VT). We conclude that EADs at the single cell level can result in different types of cardiac fibrillation at the tissue and 3D ventricle level.
[Mh] Termos MeSH primário: Ventrículos do Coração
Modelos Biológicos
[Mh] Termos MeSH secundário: Potenciais de Ação
Canais de Cálcio Tipo L/fisiologia
Seres Humanos
Canais de Sódio/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (Sodium Channels)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188867


  6 / 6897 MEDLINE  
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[PMID]:29216332
[Au] Autor:Kanatani S; Fuks JM; Olafsson EB; Westermark L; Chambers B; Varas-Godoy M; Uhlén P; Barragan A
[Ad] Endereço:Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
[Ti] Título:Voltage-dependent calcium channel signaling mediates GABAA receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii.
[So] Source:PLoS Pathog;13(12):e1006739, 2017 Dec.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection, γ-aminobutyric acid (GABA)/GABAA receptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAA receptors by GABA induces transient Ca2+ entry in DCs. Murine bone marrow-derived DCs preferentially expressed the L-type voltage-dependent Ca2+ channel (VDCC) subtype Cav1.3. Silencing of Cav1.3 by short hairpin RNA or selective pharmacological antagonism of VDCCs abolished the Toxoplasma-induced hypermigratory phenotype. In a mouse model of toxoplasmosis, VDCC inhibition of adoptively transferred Toxoplasma-infected DCs delayed the appearance of cell-associated parasites in the blood circulation and reduced parasite dissemination to target organs. The present data establish that T. gondii-induced hypermigration of DCs requires signaling via VDCCs and that Ca2+ acts as a second messenger to GABAergic signaling via the VDCC Cav1.3. The findings define a novel motility-related signaling axis in DCs and unveil that interneurons and DCs share common GABAergic motogenic pathways. T. gondii employs GABAergic non-canonical pathways to induce host cell migration and facilitate dissemination.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/imunologia
Sinalização do Cálcio
Células Dendríticas/imunologia
Receptores de GABA-A/imunologia
Toxoplasma/imunologia
Toxoplasmose/imunologia
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Movimento Celular
Células Cultivadas
Células Dendríticas/parasitologia
GABAérgicos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Toxoplasma/fisiologia
Toxoplasmose/parasitologia
Ácido gama-Aminobutírico/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cacna1d protein, mouse); 0 (Calcium Channels, L-Type); 0 (GABA Agents); 0 (Receptors, GABA-A); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006739


  7 / 6897 MEDLINE  
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[PMID]:28966273
[Au] Autor:El-Moselhy TF; Sidhom PA; Esmat EA; El-Mahdy NA
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University.
[Ti] Título:Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers.
[So] Source:Chem Pharm Bull (Tokyo);65(10):893-903, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho- or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3- and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.
[Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/síntese química
Di-Hidropiridinas/química
Di-Hidropiridinas/síntese química
[Mh] Termos MeSH secundário: Animais
Arcobacter/metabolismo
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Bloqueadores dos Canais de Cálcio/química
Bloqueadores dos Canais de Cálcio/metabolismo
Canais de Cálcio Tipo L/química
Canais de Cálcio Tipo L/metabolismo
Di-Hidropiridinas/metabolismo
Concentração Inibidora 50
Simulação de Acoplamento Molecular
Estrutura Terciária de Proteína
Relação Quantitativa Estrutura-Atividade
Coelhos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Calcium Channel Blockers); 0 (Calcium Channels, L-Type); 0 (Dihydropyridines); 0 (L-type calcium channel alpha(1C)); 7M8K3P6I89 (1,4-dihydropyridine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00186


  8 / 6897 MEDLINE  
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[PMID]:28899915
[Au] Autor:Santiago González DA; Cheli VT; Zamora NN; Lama TN; Spreuer V; Murphy GG; Paez PM
[Ad] Endereço:Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
[Ti] Título:Conditional Deletion of the L-Type Calcium Channel Cav1.2 in NG2-Positive Cells Impairs Remyelination in Mice.
[So] Source:J Neurosci;37(42):10038-10051, 2017 Oct 18.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exploring the molecular mechanisms that drive the maturation of oligodendrocyte progenitor cells (OPCs) during the remyelination process is essential to developing new therapeutic tools to intervene in demyelinating diseases such as multiple sclerosis. To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for OPC development during remyelination, we generated an inducible conditional knock-out mouse in which the L-VGCC isoform Cav1.2 was deleted in NG2-positive OPCs (Cav1.2 ). Using the cuprizone (CPZ) model of demyelination and mice of either sex, we establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. Specifically, Cav1.2 OPCs mature slower and produce less myelin than control oligodendrocytes during the recovery period after CPZ intoxication. This reduced remyelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC proliferation. Furthermore, during the remyelination phase of the CPZ model, the corpus callosum of Cav1.2 animals presented a significant decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared with controls. In addition, in a mouse line in which the Cav1.2 OPCs were identified by a reporter, we establish that Cav1.2 OPCs display a reduced maturational rate through the entire remyelination process. These results suggest that Ca influx mediated by L-VGCCs in oligodendroglial cells is necessary for normal remyelination and is an essential Ca channel for OPC maturation during the remyelination of the adult brain. Ion channels implicated in oligodendrocyte differentiation and maturation may induce positive signals for myelin recovery. Voltage-gated Ca channels (VGCCs) are important for normal myelination by acting at several critical steps during oligodendrocyte progenitor cell (OPC) development. To determine whether voltage Ca entry is involved in oligodendrocyte differentiation and remyelination, we used a conditional knockout mouse for VGCCs in OPCs. Our results indicate that VGCCs can modulate oligodendrocyte maturation in the demyelinated brain and suggest that voltage-gated Ca influx in OPCs is critical for remyelination. These findings could lead to novel approaches for obtaining a better understanding of the factors that control OPC maturation in order to stimulate this pool of progenitors to replace myelin in demyelinating diseases.
[Mh] Termos MeSH primário: Antígenos/biossíntese
Canais de Cálcio Tipo L/deficiência
Deleção de Genes
Bainha de Mielina/metabolismo
Fibras Nervosas Mielinizadas/metabolismo
Proteoglicanas/biossíntese
[Mh] Termos MeSH secundário: Animais
Antígenos/genética
Encéfalo/metabolismo
Encéfalo/patologia
Canais de Cálcio Tipo L/genética
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Bainha de Mielina/genética
Fibras Nervosas Mielinizadas/patologia
Oligodendroglia/metabolismo
Oligodendroglia/patologia
Proteoglicanas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens); 0 (CACNA1C protein, mouse); 0 (Calcium Channels, L-Type); 0 (Proteoglycans); 0 (chondroitin sulfate proteoglycan 4)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1787-17.2017


  9 / 6897 MEDLINE  
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[PMID]:28864774
[Au] Autor:Bourdin B; Briot J; Tétreault MP; Sauvé R; Parent L
[Ad] Endereço:Centre de Recherche de l'Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
[Ti] Título:Negatively charged residues in the first extracellular loop of the L-type Ca 1.2 channel anchor the interaction with the Ca α2δ1 auxiliary subunit.
[So] Source:J Biol Chem;292(42):17236-17249, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-gated L-type Ca 1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of Ca α2δ1 with Ca ß/Ca α1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the Ca 1.2/Ca α2δ1 interface are unknown. Here, a homology-based model of Ca 1.2 identified protein interfaces between the extracellular domain of Ca α2δ1 and the extracellular loops of the Ca α1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of Ca 1.2 with Ca α2δ1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with Ca α2δ1. Substitutions of Ca 1.2 Asp-181 impaired the co-immunoprecipitation of Ca ß/Ca 1.2 with Ca α2δ1 and the Ca α2δ1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in Ca 1.2 in neighboring positions in the same loop (179, 180, and 182-184) did not significantly alter the functional up-regulation of Ca 1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the Ca α2δ1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of Ca 1.2. We conclude that Ca 1.2 Asp-181 anchors the physical interaction that facilitates the Ca α2δ1-mediated functional modulation of Ca 1.2 currents. By stabilizing the first extracellular loop of Ca 1.2, Ca α2δ1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Canais de Cálcio Tipo L/genética
Canais de Cálcio Tipo L/metabolismo
Linhagem Celular
Ativação do Canal Iônico/fisiologia
Mutação de Sentido Incorreto
Miócitos Cardíacos/metabolismo
Estrutura Secundária de Proteína
Coelhos
Ratos
Sequências Repetitivas de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (L-type calcium channel alpha(1C))
[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:170903
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.806893


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[PMID]:28860353
[Au] Autor:Zheng C; Zhong M; Qi Z; Shen F; Zhao Q; Wu L; Huang Y; Tsang SY; Yao X
[Ad] Endereço:Department of Physiology, Anhui Medical University, Hefei, China (M.Z., F.S.); School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, China (C.Z.); and School of Biomedical Sciences and Li Ka Shing Institute of He
[Ti] Título:Histone Deacetylase Inhibitors Relax Mouse Aorta Partly through Their Inhibitory Action on L-Type Ca Channels.
[So] Source:J Pharmacol Exp Ther;363(2):211-220, 2017 Nov.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Histone deacetylase (HDAC) inhibitors modulate acetylation/deacetylation of histone and nonhistone proteins. They have been widely used for cancer treatment. However, there have been only a few studies investigating the effect of HDAC inhibitors on vascular tone regulation, most of which employed chronic treatment with HDAC inhibitors. In the present study, we found that two hydroxamate-based pan-HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), could partially but acutely relax high extracellular K -contracted mouse aortas. SAHA and TSA also attenuated the high extracellular K -induced cytosolic Ca rise and inhibited L-type Ca channel current in whole-cell patch-clamp. These data demonstrate that SAHA could inhibit L-type Ca channels to cause vascular relaxation. In addition, SAHA and TSA dose dependently relaxed the arteries precontracted with phenylephrine. The relaxant effect of SAHA and TSA was greater in phenylephrine-precontracted arteries than in high K -contracted arteries. Although part of the relaxant effect of SAHA and TSA on phenylephrine-precontracted arteries was related to L-type Ca channels, both agents could also induce relaxation via a mechanism independent of L-type Ca channels. Taken together, HDAC inhibitors SAHA and TSA can acutely relax blood vessels via their inhibitory action on L-type Ca channels and via another L-type Ca channel-independent mechanism.
[Mh] Termos MeSH primário: Aorta/efeitos dos fármacos
Aorta/fisiologia
Canais de Cálcio Tipo L/metabolismo
Inibidores de Histona Desacetilases/farmacologia
Ácidos Hidroxâmicos/farmacologia
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Aorta/metabolismo
Transporte Biológico/efeitos dos fármacos
Cálcio/metabolismo
Citosol/efeitos dos fármacos
Citosol/metabolismo
Fenômenos Eletrofisiológicos/efeitos dos fármacos
Espaço Extracelular/efeitos dos fármacos
Espaço Extracelular/metabolismo
Masculino
Camundongos
Músculo Liso Vascular/citologia
Músculo Liso Vascular/metabolismo
Fenilefrina/farmacologia
Potássio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 1WS297W6MV (Phenylephrine); 3X2S926L3Z (trichostatin A); 58IFB293JI (vorinostat); RWP5GA015D (Potassium); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.242685



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