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Pesquisa : D12.776.157.530.400.150.585 [Categoria DeCS]
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[PMID]:28957379
[Au] Autor:Grimaldo L; Sandoval A; Garza-López E; Felix R
[Ad] Endereço:Department of Cell Biology, Centre for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), Mexico City, Mexico.
[Ti] Título:Involvement of Parkin in the ubiquitin proteasome system-mediated degradation of N-type voltage-gated Ca2+ channels.
[So] Source:PLoS One;12(9):e0185289, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-type calcium (CaV2.2) channels are widely expressed in the brain and the peripheral nervous system, where they play important roles in the regulation of transmitter release. Although CaV2.2 channel expression levels are precisely regulated, presently little is known regarding the molecules that mediate its synthesis and degradation. Previously, by using a combination of biochemical and functional analyses, we showed that the complex formed by the light chain 1 of the microtubule-associated protein 1B (LC1-MAP1B) and the ubiquitin-proteasome system (UPS) E2 enzyme UBE2L3, may interact with the CaV2.2 channels promoting ubiquitin-mediated degradation. The present report aims to gain further insights into the possible mechanism of degradation of the neuronal CaV2.2 channel by the UPS. First, we identified the enzymes UBE3A and Parkin, members of the UPS E3 ubiquitin ligase family, as novel CaV2.2 channel binding partners, although evidence to support a direct protein-protein interaction is not yet available. Immunoprecipitation assays confirmed the interaction between UBE3A and Parkin with CaV2.2 channels heterologously expressed in HEK-293 cells and in neural tissues. Parkin, but not UBE3A, overexpression led to a reduced CaV2.2 protein level and decreased current density. Electrophysiological recordings performed in the presence of MG132 prevented the actions of Parkin suggesting enhanced channel proteasomal degradation. Together these results unveil a novel functional coupling between Parkin and the CaV2.2 channels and provide a novel insight into the basic mechanisms of CaV channels protein quality control and functional expression.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteólise
Ubiquitina-Proteína Ligases/metabolismo
Ubiquitina/metabolismo
[Mh] Termos MeSH secundário: Animais
Membrana Celular/metabolismo
Gânglios Espinais/metabolismo
Técnicas de Silenciamento de Genes
Células HEK293
Seres Humanos
Ativação do Canal Iônico
Camundongos Endogâmicos BALB C
Proteínas Associadas aos Microtúbulos/metabolismo
Ligação Proteica
Subunidades Proteicas/metabolismo
Coelhos
Ratos
Proteínas Recombinantes/metabolismo
Enzimas de Conjugação de Ubiquitina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, N-Type); 0 (MAP1B protein, human); 0 (Microtubule-Associated Proteins); 0 (Protein Subunits); 0 (Recombinant Proteins); 0 (Ubiquitin); EC 2.3.2.23 (UBE2L3 protein, human); EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes); EC 2.3.2.26 (UBE3A protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (parkin protein); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185289


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[PMID]:28882644
[Au] Autor:Weon H; Kim TW; Youn DH
[Ad] Endereço:Department of Oral Physiology, BioCure Laboratory, School of Dentistry, Kyungpook National University, 2177 Dalgubeol Blvd, Jung-gu, Daegu 41940, Republic of Korea.
[Ti] Título:Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.
[So] Source:Life Sci;188:110-117, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Both N-type and P/Q-type voltage-gated Ca channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). MAIN METHODS: (S)-3,5-Dihydroxyphenylglycine (DHPG; 10µM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. KEY FINDINGS: Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. SIGNIFICANCE: Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/fisiologia
Canais de Cálcio Tipo P/fisiologia
Canais de Cálcio Tipo Q/fisiologia
Potenciação de Longa Duração/fisiologia
Receptores de Glutamato Metabotrópico/fisiologia
Núcleo Espinal do Trigêmeo/fisiologia
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Animais
Agonistas dos Canais de Cálcio/farmacologia
Bloqueadores dos Canais de Cálcio
Cromonas/farmacologia
Feminino
Potenciação de Longa Duração/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/fisiologia
Masculino
Terminações Pré-Sinápticas/fisiologia
Ratos
Receptores de Glutamato Metabotrópico/agonistas
Potenciais Sinápticos/fisiologia
Transmissão Sináptica/efeitos dos fármacos
Núcleo Espinal do Trigêmeo/efeitos dos fármacos
ômega-Conotoxinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((S)-3,7-dihydroxychroman-4-one); 0 (Agatoxins); 0 (Calcium Channel Agonists); 0 (Calcium Channel Blockers); 0 (Calcium Channels, N-Type); 0 (Calcium Channels, P-Type); 0 (Calcium Channels, Q-Type); 0 (Chromones); 0 (Receptors, Metabotropic Glutamate); 0 (omega-Conotoxins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE


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[PMID]:28880874
[Au] Autor:Sousa SR; Wingerd JS; Brust A; Bladen C; Ragnarsson L; Herzig V; Deuis JR; Dutertre S; Vetter I; Zamponi GW; King GF; Alewood PF; Lewis RJ
[Ad] Endereço:IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
[Ti] Título:Discovery and mode of action of a novel analgesic ß-toxin from the African spider Ceratogyrus darlingi.
[So] Source:PLoS One;12(9):e0182848, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 µM) but not Cav1.3 or Cav3.1 (IC50 > 30 µM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 µM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker ω-conotoxin GVIA, but its activity at Cav2.2-mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 µM) but not Nav1.3-1.6 (IC50 > 30 µM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 α-subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Venenos de Aranha/química
Aranhas/química
[Mh] Termos MeSH secundário: Analgésicos/química
Animais
Sítios de Ligação/efeitos dos fármacos
Canais de Cálcio Tipo N/metabolismo
Eletrofisiologia
Fluorometria
Seres Humanos
Camundongos
Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Peptídeos/química
Peptídeos/farmacologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Cacna1b protein, rat); 0 (Calcium Channels, N-Type); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Peptides); 0 (Spider Venoms)
[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:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182848


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[PMID]:28669545
[Au] Autor:Tong XJ; López-Soto EJ; Li L; Liu H; Nedelcu D; Lipscombe D; Hu Z; Kaplan JM
[Ad] Endereço:Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:Retrograde Synaptic Inhibition Is Mediated by α-Neurexin Binding to the α2δ Subunits of N-Type Calcium Channels.
[So] Source:Neuron;95(2):326-340.e5, 2017 Jul 19.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The synaptic adhesion molecules Neurexin and Neuroligin alter the development and function of synapses and are linked to autism in humans. In C. elegans, post-synaptic Neurexin (NRX-1) and pre-synaptic Neuroligin (NLG-1) mediate a retrograde synaptic signal that inhibits acetylcholine (ACh) release at neuromuscular junctions. Here, we show that the retrograde signal decreases ACh release by inhibiting the function of pre-synaptic UNC-2/CaV2 calcium channels. Post-synaptic NRX-1 binds to an auxiliary subunit of pre-synaptic UNC-2/CaV2 channels (UNC-36/α2δ), decreasing UNC-36 abundance at pre-synaptic elements. Retrograde inhibition is mediated by a soluble form of NRX-1's ectodomain, which is released from the post-synaptic membrane by the SUP-17/ADAM10 protease. Mammalian Neurexin-1α binds α2δ-3 and decreases CaV2.2 current in transfected cells, whereas Neurexin-1α has no effect on CaV2.2 reconstituted with α2δ-1 and α2δ-2. Collectively, these results suggest that α-Neurexin binding to α2δ is a conserved mechanism for regulating synaptic transmission.
[Mh] Termos MeSH primário: Fenômenos Biofísicos/fisiologia
Canais de Cálcio Tipo N/metabolismo
Glicoproteínas/metabolismo
Neuropeptídeos/metabolismo
Sinapses/metabolismo
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Animais
Caenorhabditis elegans
Proteínas de Caenorhabditis elegans/metabolismo
Moléculas de Adesão Celular Neuronais/metabolismo
Seres Humanos
Proteínas do Tecido Nervoso/metabolismo
Junção Neuromuscular/metabolismo
Subunidades Proteicas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Calcium Channels, N-Type); 0 (Cell Adhesion Molecules, Neuronal); 0 (Glycoproteins); 0 (Nerve Tissue Proteins); 0 (Neuropeptides); 0 (Protein Subunits); 0 (neurexophilin); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE


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[PMID]:28389298
[Au] Autor:Rajagopal S; Burton BK; Fields BL; El IO; Kamatchi GL
[Ad] Endereço:Department of Biology, Norfolk State University, Norfolk, VA 23504, USA.
[Ti] Título:Stimulatory and inhibitory effects of PKC isozymes are mediated by serine/threonine PKC sites of the Ca 2.3α subunits.
[So] Source:Arch Biochem Biophys;621:24-30, 2017 May 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein kinase C (PKC) isozymes modulate voltage-gated calcium (Ca ) currents through Ca 2.2 and Ca 2.3 channels by targeting serine/threonine (Ser/Thr) phosphorylation sites of Ca α subunits. Stimulatory (Thr-422, Ser-2108 and Ser-2132) and inhibitory (Ser-425) sites were identified in the Ca 2.2α subunits to PKCs ßII and ε. In the current study, we investigated if the homologous sites of Ca 2.3α subunits (stimulatory: Thr-365, Ser-1995 and Ser-2011; inhibitory: Ser-369) behaved in similar manner. Several Ala and Asp mutants were constructed in Ca 2.3α subunits in such a way that the Ser/Thr sites can be examined in isolation. These mutants or WT Ca 2.3α along with auxiliary ß and α /δ subunits were expressed in Xenopus oocytes and the effects of PKCs ßII and ε studied on the barium current (I ). Among these sites, stimulatory Thr-365 and Ser-1995 and inhibitory Ser-369 behaved similar to their homologs in Ca 2.2α subunits. Furthermore PKCs produced neither stimulation nor inhibition when stimulatory Thr-365 or Ser-1995 and inhibitory Ser-369 were present together. However, the PKCs potentiated the I when two stimulatory sites, Thr-365 and Ser-1995 were present together, thus overcoming the inhibitory effect of Ser-369. Taken together net PKC effect may be the difference between the responses of the stimulatory and inhibitory sites.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/química
Canais de Cálcio Tipo N/metabolismo
Potenciais da Membrana/fisiologia
Oócitos/fisiologia
Proteína Quinase C/química
Proteína Quinase C/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Células Cultivadas
Ativação Enzimática
Inibidores Enzimáticos
Isoenzimas/química
Isoenzimas/metabolismo
Mutagênese Sítio-Dirigida
Ligação Proteica
Subunidades Proteicas
Serina/química
Serina/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Treonina/química
Treonina/metabolismo
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, N-Type); 0 (Enzyme Inhibitors); 0 (Isoenzymes); 0 (Protein Subunits); 0 (voltage-dependent calcium channel (P-Q type)); 2ZD004190S (Threonine); 452VLY9402 (Serine); EC 2.7.11.13 (Protein Kinase C)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170909
[Lr] Data última revisão:
170909
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE


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[PMID]:28377503
[Au] Autor:Hirano M; Takada Y; Wong CF; Yamaguchi K; Kotani H; Kurokawa T; Mori MX; Snutch TP; Ronjat M; De Waard M; Mori Y
[Ad] Endereço:From the Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, and.
[Ti] Título:C-terminal splice variants of P/Q-type Ca channel Ca 2.1 α subunits are differentially regulated by Rab3-interacting molecule proteins.
[So] Source:J Biol Chem;292(22):9365-9381, 2017 Jun 02.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-dependent Ca channels (VDCCs) mediate neurotransmitter release controlled by presynaptic proteins such as the scaffolding proteins Rab3-interacting molecules (RIMs). RIMs confer sustained activity and anchoring of synaptic vesicles to the VDCCs. Multiple sites on the VDCC α and ß subunits have been reported to mediate the RIMs-VDCC interaction, but their significance is unclear. Because alternative splicing of exons 44 and 47 in the P/Q-type VDCC α subunit Ca 2.1 gene generates major variants of the Ca 2.1 C-terminal region, known for associating with presynaptic proteins, we focused here on the protein regions encoded by these two exons. Co-immunoprecipitation experiments indicated that the C-terminal domain (CTD) encoded by Ca 2.1 exons 40-47 interacts with the α-RIMs, RIM1α and RIM2α, and this interaction was abolished by alternative splicing that deletes the protein regions encoded by exons 44 and 47. Electrophysiological characterization of VDCC currents revealed that the suppressive effect of RIM2α on voltage-dependent inactivation (VDI) was stronger than that of RIM1α for the Ca 2.1 variant containing the region encoded by exons 44 and 47. Importantly, in the Ca 2.1 variant in which exons 44 and 47 were deleted, strong RIM2α-mediated VDI suppression was attenuated to a level comparable with that of RIM1α-mediated VDI suppression, which was unaffected by the exclusion of exons 44 and 47. Studies of deletion mutants of the exon 47 region identified 17 amino acid residues on the C-terminal side of a polyglutamine stretch as being essential for the potentiated VDI suppression characteristic of RIM2α. These results suggest that the interactions of the Ca 2.1 CTD with RIMs enable Ca 2.1 proteins to distinguish α-RIM isoforms in VDI suppression of P/Q-type VDCC currents.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/metabolismo
Canais de Cálcio/metabolismo
Proteínas de Ligação ao GTP/metabolismo
Proteínas do Tecido Nervoso/metabolismo
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio/genética
Canais de Cálcio Tipo N/genética
Proteínas de Ligação ao GTP/genética
Células HEK293
Seres Humanos
Camundongos
Proteínas do Tecido Nervoso/genética
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CACNA1A protein, human); 0 (Calcium Channels); 0 (Calcium Channels, N-Type); 0 (Nerve Tissue Proteins); 0 (RIMS1 protein, human); 0 (Rims1 protein, mouse); 0 (Rims2 protein, mouse); 0 (voltage-dependent calcium channel (P-Q type)); EC 3.6.1.- (GTP-Binding Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.778829


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[PMID]:28202361
[Au] Autor:Nicoletti NF; Erig TC; Zanin RF; Roxo MR; Ferreira NP; Gomez MV; Morrone FB; Campos MM
[Ad] Endereço:PUCRS, Programa de Pós-Graduação em Biologia Celular e Molecular, Porto Alegre, RS, Brazil; PUCRS, Instituto de Toxicologia e Farmacologia, Porto Alegre, RS, Brazil.
[Ti] Título:Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression.
[So] Source:Toxicon;129:58-67, 2017 Apr.
[Is] ISSN:1879-3150
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:This study investigated the effects of P/Q- and N-type voltage-gated calcium channel (VGCC) blockers derived from P. nigriventer in glioma progression, by means of in vitro and in vivo experiments. Glioma cells M059J, U-138MG and U-251MG were used to evaluate the antiproliferative effects of P/Q- and N-type VGCC inhibitors PhTx3-3 and Phα1ß from P. nigriventer (0.3-100 pM), in comparison to MVIIC and MVIIA from C. magus (0.3-100 pM), respectively. The toxins were also analyzed in a glioma model induced by implantation of GL261 mouse cells. PhTx3-3, Phα1ß and MVIIA displayed significant inhibitory effects on the proliferation and viability of all tested glioma cell lines, and evoked cell death mainly with apoptosis characteristics, as indicated by Annexin V/propidium iodide (PI) positivity. The antiproliferative effects of toxins were confirmed by flow cytometry using Ki67 staining. None of the tested toxins altered the proliferation rates of the N9 non-tumor glial cell line. Noteworthy, the administration of the preferential N-type VGCC inhibitors, Phα1ß (50 pmol/site; i.c.v.), its recombinant form CTK 01512-2 (50 pmol/site; i.c.v. and i.t.), or MVIIA (10 pmol/site; i.c.v.) caused significant reductions of tumor areas in vivo. N-type VGCC inhibition by Phα1ß, CTK 01512-2, and MVIIA led to a marked increase of GFAP-activated astrocytes, and Iba-1-positive microglia, in the peritumoral region, which might explain, at least in part, the inhibitory effects of the toxins in tumor development. This study provides novel evidence on the potential effects of P. nigriventer-derived P/Q-, and mainly, N-type VGCC inhibitors, in glioma progression.
[Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/farmacologia
Neuropeptídeos/farmacologia
Venenos de Aranha/farmacologia
Aranhas/química
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio Tipo N/efeitos dos fármacos
Canais de Cálcio Tipo N/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Glioma/tratamento farmacológico
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels, N-Type); 0 (Neuropeptides); 0 (Spider Venoms); 0 (Tx1 neurotoxin); 0 (Tx3 neurotoxin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE


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[PMID]:28167673
[Au] Autor:Fu SJ; Jeng CJ; Ma CH; Peng YJ; Lee CM; Fang YC; Lee YC; Tang SC; Hu MC; Tang CY
[Ad] Endereço:Department of Physiology and.
[Ti] Título:Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca 2.1 (P/Q-Type) Calcium Channels.
[So] Source:J Neurosci;37(9):2485-2503, 2017 Mar 01.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-gated Ca 2.1 channels comprise a pore-forming α subunit with auxiliary α δ and ß subunits. Ca 2.1 channels play an essential role in regulating synaptic signaling. Mutations in the human gene encoding the Ca 2.1 subunit are associated with the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of Ca 2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human Ca 2.1 subunit by identifying RNF138, an E3 ubiquitin ligase, as a novel Ca 2.1-binding partner. In neurons, RNF138 and Ca 2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of Ca 2.1. Disrupting endogenous RNF138 function with a mutant (RNF138-H36E) or shRNA infection significantly upregulates the Ca 2.1 protein level and enhances Ca 2.1 protein stability. Disrupting endogenous RNF138 function also effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of Ca 2.1 WT subunits. RNF138-H36E coexpression only partially restores the dominant-negative effect of EA2 mutants on Ca 2.1 WT functional expression, which can be attributed to defective membrane trafficking of Ca 2.1 WT in the presence of EA2 mutants. We propose that RNF138 plays a critical role in the homeostatic regulation of Ca 2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human Ca 2.1 subunits. Loss-of-function mutations in the human Ca 2.1 subunit are linked to episodic ataxia type 2 (EA2), a dominantly inherited disease characterized by paroxysmal attacks of ataxia and nystagmus. EA2-causing mutants may exert dominant-negative effects on the Ca 2.1 wild-type subunit via aberrant proteasomal degradation. The molecular nature of the Ca 2.1 ubiquitin-proteasome degradation pathway is currently unknown. The present study reports the first identification of an E3 ubiquitin ligase for Ca 2.1, RNF138. Ca 2.1 protein stability is dynamically regulated by RNF138 and auxiliary α δ and ß subunits. We provide a proof of concept that protecting the human Ca 2.1 subunit from excessive proteasomal degradation with specific interruption of endogenous RNF138 function may partially contribute to the future development of a novel therapeutic strategy for EA2 patients.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
[Mh] Termos MeSH secundário: Animais
Ataxia/genética
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/ultraestrutura
Canais de Cálcio Tipo N/genética
Linhagem Celular
Células Cultivadas
Córtex Cerebral/citologia
Cicloeximida/farmacologia
Células HEK293
Seres Humanos
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/genética
Mutação/genética
Neuroblastoma/patologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Nistagmo Patológico/genética
Oócitos
Inibidores da Síntese de Proteínas/farmacologia
Proteólise/efeitos dos fármacos
Frações Subcelulares/efeitos dos fármacos
Frações Subcelulares/metabolismo
Ubiquitinação/efeitos dos fármacos
Ubiquitinação/genética
Xenopus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CACNA1B protein, human); 0 (Calcium Channels, N-Type); 0 (Protein Synthesis Inhibitors); 98600C0908 (Cycloheximide); EC 2.3.2.27 (RNF138 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[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:170208
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3070-16.2017


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[PMID]:28132918
[Au] Autor:Lu CW; Lin TY; Chang CY; Huang SK; Wang SJ
[Ad] Endereço:Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan.
[Ti] Título:Ciproxifan, a histamine H receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus.
[So] Source:Toxicol Appl Pharmacol;319:12-21, 2017 Mar 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ciproxifan is an H receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca -dependent glutamate release and cytosolic Ca concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Ca 2.2 (N-type) and Ca 2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca -release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A (PLA ) inhibitor OBAA, prostaglandin E (PGE ), PGE2 subtype 2 (EP ) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca entry by diminishing PLA /PGE /EP receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.
[Mh] Termos MeSH primário: Agonismo Inverso de Drogas
Ácido Glutâmico/secreção
Hipocampo/secreção
Antagonistas dos Receptores Histamínicos H3/farmacologia
Imidazóis/farmacologia
Terminações Pré-Sinápticas/secreção
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio Tipo N/secreção
Relação Dose-Resposta a Droga
Hipocampo/efeitos dos fármacos
Masculino
Camundongos
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Técnicas de Cultura de Órgãos
Terminações Pré-Sinápticas/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, N-Type); 0 (Histamine H3 Antagonists); 0 (Imidazoles); 0 (voltage-dependent calcium channel (P-Q type)); 3KX376GY7L (Glutamic Acid); 5EVQ7IRG99 (ciproxifan)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


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[PMID]:28131838
[Au] Autor:Kim YH; Jeong JH; Ahn DS; Chung S
[Ad] Endereço:Department of Physiology, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
[Ti] Título:Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate underlies agmatine-induced suppression of N-type Ca channel in rat celiac ganglion neurons.
[So] Source:Biochem Biophys Res Commun;484(2):342-347, 2017 Mar 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agmatine suppresses peripheral sympathetic tone by modulating Cav2.2 channels in peripheral sympathetic neurons. However, the detailed cellular signaling mechanism underlying the agmatine-induced Cav2.2 inhibition remains unclear. Therefore, in the present study, we investigated the electrophysiological mechanism for the agmatine-induced inhibition of Cav2.2 current (I ) in rat celiac ganglion (CG) neurons. Consistent with previous reports, agmatine inhibited I in a VI manner. The agmatine-induced inhibition of the I current was also almost completely hindered by the blockade of the imidazoline I receptor (IR ), and an IR agonist mimicked the inhibitory effect of agmatine on I , implying involvement of IR . The agmatine-induced I inhibition was significantly hampered by the blockade of G protein or phospholipase C (PLC), but not by the pretreatment with pertussis toxin. In addition, diC8-phosphatidylinositol 4,5-bisphosphate (PIP ) dialysis nearly completely hampered agmatine-induced inhibition, which became irreversible when PIP resynthesis was blocked. These results suggest that in rat peripheral sympathetic neurons, agmatine-induced IR activation suppresses Cav2.2 channel voltage-independently, and that the PLC-dependent PIP hydrolysis is responsible for the agmatine-induced suppression of the Cav2.2 channel.
[Mh] Termos MeSH primário: Agmatina/farmacologia
Canais de Cálcio Tipo N/efeitos dos fármacos
Gânglios Simpáticos/efeitos dos fármacos
Fosfatidilinositol 4,5-Difosfato/metabolismo
Fosfolipases Tipo C/metabolismo
[Mh] Termos MeSH secundário: Abdome
Animais
Bloqueadores dos Canais de Cálcio/farmacologia
Gânglios Simpáticos/metabolismo
Hidrólise
Masculino
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels, N-Type); 0 (Phosphatidylinositol 4,5-Diphosphate); 70J407ZL5Q (Agmatine); EC 3.1.4.- (Type C Phospholipases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170130
[St] Status:MEDLINE



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