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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]:27702646
[Au] Autor:Martin-Cortecero J; Nuñez A
[Ad] Endereço:Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
[Ti] Título:Sensory responses in the medial prefrontal cortex of anesthetized rats. Implications for sensory processing.
[So] Source:Neuroscience;339:109-123, 2016 Dec 17.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The medial prefrontal cortex (mPFC) plays a key role in higher functions such as memory and attention. In order to demonstrate sensory responses in the mPFC, we used electrophysiological recordings of urethane-anesthetized rats to record somatosensory-evoked potentials (SEPs) or auditory-evoked potentials (AEPs) elicited by whisker deflections and click stimulation, respectively. Contralateral whisker stimulation or auditory stimuli were also applied to study sensory interference in the mPFC. Interference with other sensory stimuli or recent stimulation history reduced whisker responses in the infralimbic and prelimbic cortices of the ventral mPFC. This effect could be mediated by activation of parvalbumin (PV) interneurons since the effect was blocked by the P/Q calcium channel antagonist ω-agatoxin. In contrast, sensory interference or the recent stimulation history was not detected by the dorsal mPFC or the primary somatosensory cortex. Results obtained from retrograde tracer injections in the dorsal and ventral regions of the mPFC indicated that somatosensory and auditory sensory inputs may arrive at the dorsal mPFC through secondary sensory cortical areas, and through the insular and temporal cortical areas. The ventral mPFC may receive sensory information through the strong anatomical connections between the dorsal and ventral mPFC areas. In conclusion, results suggest mPFC plays an important role in sensory processing, which may have important implications in attentional and memory processes.
[Mh] Termos MeSH primário: Percepção Auditiva/fisiologia
Córtex Pré-Frontal/fisiologia
Percepção do Tato/fisiologia
[Mh] Termos MeSH secundário: Adaptação Fisiológica/efeitos dos fármacos
Adaptação Fisiológica/fisiologia
Agatoxinas/farmacologia
Anestésicos Intravenosos/farmacologia
Animais
Percepção Auditiva/efeitos dos fármacos
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo P/metabolismo
Canais de Cálcio Tipo Q/metabolismo
Potenciais Evocados Auditivos/efeitos dos fármacos
Potenciais Evocados Auditivos/fisiologia
Potenciais Somatossensoriais Evocados/efeitos dos fármacos
Potenciais Somatossensoriais Evocados/fisiologia
Feminino
Masculino
Neurônios/citologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Córtex Pré-Frontal/citologia
Córtex Pré-Frontal/efeitos dos fármacos
Ratos Sprague-Dawley
Percepção do Tato/efeitos dos fármacos
Uretana/farmacologia
Vibrissas/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agatoxins); 0 (Anesthetics, Intravenous); 0 (Calcium Channel Blockers); 0 (Calcium Channels, P-Type); 0 (Calcium Channels, Q-Type); 3IN71E75Z5 (Urethane)
[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:161105
[St] Status:MEDLINE


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[PMID]:26626629
[Au] Autor:Sturm S; Ramesh D; Brockmann A; Neupert S; Predel R
[Ad] Endereço:Institute for Zoology, University of Cologne, Zuelpicher Str. 47b, 50674 Cologne, Germany.
[Ti] Título:Agatoxin-like peptides in the neuroendocrine system of the honey bee and other insects.
[So] Source:J Proteomics;132:77-84, 2016 Jan 30.
[Is] ISSN:1876-7737
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: We investigated the peptide inventory of the corpora cardiaca (CC) of the honey bee, Apis mellifera, by direct tissue profiling using MALDI-TOF MS combined with proteomic approaches focusing on cysteine-containing peptides. An agatoxin-like peptide (ALP) was identified as a component of the glandular part of the CC and was associated with the presence of the adipokinetic hormone in mass spectra. Although abundant in the CC, ALP does not belong to the toxins observed in the venom gland of A. mellifera. Homologs of ALP are highly conserved in major groups of arthropods and in line with this we detected ALP in the CC of non-venomous insects such as cockroaches and silverfish. In the American cockroach, Periplaneta americana, ALP was also identified in the CNS and stomatogastric nervous system. This is the first report that establishes the presence of ALPs in the neuroendocrine tissues of insects and further studies are necessary to reveal common functions of these peptides, e.g. as antimicrobial agents, ion channel modulators or classical neuropeptides. BIOLOGICAL SIGNIFICANCE: Among the messenger molecules of the nervous system, neuropeptides represent the structurally most diverse class and basically participate in the regulation of all physiological processes. The set of neuropeptides, their functions and spatial distribution are particularly well-studied in insects. Until now, however, several potential neuropeptide receptors remained orphan, which indicates the existence of so far unknown ligands. In our study, we used proteomic methods such as cysteine modification, enzymatic digestion and peptide derivatization, combined with direct tissue profiling by MALDI-TOF mass spectrometry, for the discovery of novel putative messenger molecules in the neuroendocrine system. The described presence of agatoxin-like peptides in the nervous system of the honey bee and other insects was overseen so far and is thus a remarkable addition to the very well studied neuropeptidome of insects. It is not yet clear, if these toxin-like peptides act as antimicrobial agents, ion channel modulators or classical neuropeptides.
[Mh] Termos MeSH primário: Agatoxinas/química
Agatoxinas/metabolismo
Abelhas/metabolismo
Insetos/metabolismo
Sistemas Neurossecretores/metabolismo
Peptídeos/química
[Mh] Termos MeSH secundário: Agatoxinas/análise
Sequência de Aminoácidos
Animais
Sequência Conservada
Dados de Sequência Molecular
Peptídeos/análise
Peptídeos/metabolismo
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Agatoxins); 0 (Peptides)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151203
[St] Status:MEDLINE


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[PMID]:25143618
[Au] Autor:Schlingloff D; Káli S; Freund TF; Hájos N; Gulyás AI
[Ad] Endereço:Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, János Szentágothai PhD Program of Semmelweis University, H-1085 Budapest, Hungary.
[Ti] Título:Mechanisms of sharp wave initiation and ripple generation.
[So] Source:J Neurosci;34(34):11385-98, 2014 Aug 20.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Replay of neuronal activity during hippocampal sharp wave-ripples (SWRs) is essential in memory formation. To understand the mechanisms underlying the initiation of irregularly occurring SWRs and the generation of periodic ripples, we selectively manipulated different components of the CA3 network in mouse hippocampal slices. We recorded EPSCs and IPSCs to examine the buildup of neuronal activity preceding SWRs and analyzed the distribution of time intervals between subsequent SWR events. Our results suggest that SWRs are initiated through a combined refractory and stochastic mechanism. SWRs initiate when firing in a set of spontaneously active pyramidal cells triggers a gradual, exponential buildup of activity in the recurrent CA3 network. We showed that this tonic excitatory envelope drives reciprocally connected parvalbumin-positive basket cells, which start ripple-frequency spiking that is phase-locked through reciprocal inhibition. The synchronized GABA(A) receptor-mediated currents give rise to a major component of the ripple-frequency oscillation in the local field potential and organize the phase-locked spiking of pyramidal cells. Optogenetic stimulation of parvalbumin-positive cells evoked full SWRs and EPSC sequences in pyramidal cells. Even with excitation blocked, tonic driving of parvalbumin-positive cells evoked ripple oscillations. Conversely, optogenetic silencing of parvalbumin-positive cells interrupted the SWRs or inhibited their occurrence. Local drug applications and modeling experiments confirmed that the activity of parvalbumin-positive perisomatic inhibitory neurons is both necessary and sufficient for ripple-frequency current and rhythm generation. These interneurons are thus essential in organizing pyramidal cell activity not only during gamma oscillation, but, in a different configuration, during SWRs.
[Mh] Termos MeSH primário: Potenciais de Ação/fisiologia
Região CA3 Hipocampal/citologia
Região CA3 Hipocampal/fisiologia
Neurônios/fisiologia
Potenciais Evocados Miogênicos Vestibulares/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Agatoxinas/farmacologia
Anestésicos Locais/farmacologia
Animais
Animais Recém-Nascidos
Anquirinas/metabolismo
Região CA3 Hipocampal/efeitos dos fármacos
Bloqueadores dos Canais de Cálcio/farmacologia
Channelrhodopsins
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos
Feminino
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Masculino
Camundongos
Camundongos Transgênicos
Modelos Neurológicos
Neurônios/efeitos dos fármacos
Parvalbuminas/genética
Detecção de Sinal Psicológico
Tetrodotoxina/farmacologia
Potenciais Evocados Miogênicos Vestibulares/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Agatoxins); 0 (Anesthetics, Local); 0 (Ank3 protein, mouse); 0 (Ankyrins); 0 (Calcium Channel Blockers); 0 (Channelrhodopsins); 0 (Parvalbumins); 4368-28-9 (Tetrodotoxin)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140822
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0867-14.2014


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[PMID]:24849341
[Au] Autor:Di Guilmi MN; Wang T; Inchauspe CG; Forsythe ID; Ferrari MD; van den Maagdenberg AM; Borst JG; Uchitel OD
[Ad] Endereço:Institute of Physiology, Molecular Biology and Neuroscience (IFIBYNE, UBA-CONICET), Department of Physiology, Molecular, and Cell Biology, University of Buenos Aires, Buenos Aires C1428EHA, Argentina.
[Ti] Título:Synaptic gain-of-function effects of mutant Cav2.1 channels in a mouse model of familial hemiplegic migraine are due to increased basal [Ca2+]i.
[So] Source:J Neurosci;34(21):7047-58, 2014 May 21.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Specific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated CaV2.1 channels, are associated with familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of common migraine with aura. We used transgenic knock-in (KI) mice harboring the human pathogenic FHM1 mutation S218L to study presynaptic Ca(2+) currents, EPSCs, and in vivo activity at the calyx of Held synapse. Whole-cell patch-clamp recordings of presynaptic terminals from S218L KI mice showed a strong shift of the calcium current I-V curve to more negative potentials, leading to an increase in basal [Ca(2+)]i, increased levels of spontaneous transmitter release, faster recovery from synaptic depression, and enhanced synaptic strength despite smaller action-potential-elicited Ca(2+) currents. The gain-of-function of transmitter release of the S218L mutant was reproduced in vivo, including evidence for an increased release probability, demonstrating its relevance for glutamatergic transmission. This synaptic phenotype may explain the misbalance between excitation and inhibition in neuronal circuits resulting in a persistent hyperexcitability state and other migraine-relevant mechanisms such as an increased susceptibility to cortical spreading depression.
[Mh] Termos MeSH primário: Tronco Encefálico/fisiologia
Canais de Cálcio Tipo N/genética
Cálcio/metabolismo
Enxaqueca com Aura/genética
Enxaqueca com Aura/metabolismo
Mutação/genética
Sinapses/fisiologia
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Animais
Tronco Encefálico/citologia
Modelos Animais de Doenças
Seres Humanos
Técnicas In Vitro
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Enxaqueca com Aura/patologia
Enxaqueca com Aura/fisiopatologia
Neurotoxinas/farmacologia
Bloqueadores dos Canais de Sódio/farmacologia
Sinapses/efeitos dos fármacos
Sinapses/genética
Tetrodotoxina/farmacologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Agatoxins); 0 (Calcium Channels, N-Type); 0 (Neurotoxins); 0 (Sodium Channel Blockers); 0 (voltage-dependent calcium channel (P-Q type)); 4368-28-9 (Tetrodotoxin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1407
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140523
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2526-13.2014


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[PMID]:24505607
[Au] Autor:Recillas-Morales S; Sánchez-Vega L; Ochoa-Sánchez N; Caballero-Florán I; Paz-Bermúdez F; Silva I; Aceves J; Erlij D; Florán B
[Ti] Título:L-type Ca²âº channel activity determines modulation of GABA release by dopamine in the substantia nigra reticulata and the globus pallidus of the rat.
[So] Source:Neuroscience;256:292-301, 2014 Jan 03.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Modulation of L-type Ca²âº-channel function by dopamine is a major determinant of the rate of action potential firing by striatal medium spiny neurons. However, the role of these channels in modulating GABA release by nerve terminals in the basal ganglia is unknown. We found that depolarization-induced [³H]GABA release in both the substantia nigra reticulata and the external globus pallidus (GPe), was depressed by about 50% by either the selective L-channel dihydropyridine blocker nifedipine or the P/Q channel blocker ω-agatoxin TK. The effects of these blockers were additive and together eliminated about 90% of depolarization-induced [³H]GABA release. In addition, in the substantia nigra reticulata, dihydropyridines prevented both the stimulation of [³H]GABA release produced by dopamine D1 receptor activation and the inhibition caused by D4 receptor activation. In the GP nifedipine blocked the effects of D2 and A2(A) receptor coactivation as well as the effects of activating adenylyl cyclase with forskolin. ω-Agatoxin TK did not interfere with the action of these modulatory agents. The L-type Ca²âº-channel agonist BAYK 8644 stimulated GABA release in both substantia nigra reticulata and GP. Because dihydropyridine sensitivity is a key criterion to identify L-type Ca²âº-channel activity, our results imply that these channels are determinant of GABA release modulation by dopamine in striatonigral, striatopallidal and pallidonigral terminals.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/metabolismo
Dopamina/farmacologia
Globo Pálido/efeitos dos fármacos
Substância Negra/efeitos dos fármacos
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia
Agatoxinas/farmacologia
Análise de Variância
Animais
Agonistas dos Canais de Cálcio/farmacologia
Dopaminérgicos/farmacologia
Técnicas In Vitro
Masculino
Nifedipino/farmacologia
Cloreto de Potássio/farmacologia
Ratos
Ratos Wistar
Trítio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Agatoxins); 0 (Calcium Channel Agonists); 0 (Calcium Channels, L-Type); 0 (Dopamine Agents); 0 (omega-agatoxin-Aa4b); 10028-17-8 (Tritium); 56-12-2 (gamma-Aminobutyric Acid); 660YQ98I10 (Potassium Chloride); 71145-03-4 (3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester); I9ZF7L6G2L (Nifedipine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140208
[St] Status:MEDLINE


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[PMID]:23817128
[Au] Autor:Wagner-Britz L; Wang J; Kaestner L; Bernhardt I
[Ad] Endereço:Laboratory of Biophysics, Faculty of Natural and Technical Sciences III, Saarland University, Saarbrücken, Germany.
[Ti] Título:Protein kinase Cα and P-type Ca channel CaV2.1 in red blood cell calcium signalling.
[So] Source:Cell Physiol Biochem;31(6):883-91, 2013.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Protein kinase Cα (PKCα) is activated by an increase in cytosolic Ca(2+) in red blood cells (RBCs). Previous work has suggested that PKCα directly stimulates the CaV2.1 channel, whereas other studies revealed that CaV2.1 is insensitive to activation by PKC. The aim of this study was to resolve this discrepancy. METHODS: We performed experiments based on a single cell read-out of the intracellular Ca(2+) concentration in terms of Fluo-4 fluorescence intensity and phosphatidylserine exposure to the external membrane leaflet. Measurement modalities included flow cytometry and live cell imaging. RESULTS: Treatment of RBCs with phorbol 12-myristate 13-acetate (PMA) led to two distinct populations of cells with an increase in intracellular Ca(2+): a weak-responding and a strong-responding population. The EC50 of PMA for the number of cells with Ca(2+) elevation was 2.7±1.2 µM; for phosphatidylserine exposure to the external membrane surface, it was 2.8±0.5 µM; and for RBC haemolysis, it was 2.9±0.5 µM. Using pharmacological manipulation with the CaV2.1 inhibitor ω-agatoxin TK and the broad protein kinase C inhibitor Gö6983, we are able to show that there are two independent PMA-activated Ca(2+) entry processes: the first is independent of CaV2.1 and directly PKCα-activated, while the second is associated with a likely indirect activation of CaV2.1. Further studies using lysophosphatidic acid (LPA) as a stimulation agent have provided additional evidence that PKCα and CaV2.1 are not directly interconnected in a signalling chain. CONCLUSION: Although we provide evidence for a lack of interaction between PKCα and CaV2.1 in RBCs, further studies are required to decipher the signalling relationship between LPA, PKCα and CaV2.1.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo N/metabolismo
Eritrócitos/metabolismo
Proteína Quinase C-alfa/metabolismo
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Compostos de Anilina/química
Cálcio/metabolismo
Canais de Cálcio Tipo N/química
Sinalização do Cálcio/efeitos dos fármacos
Membrana Celular/efeitos dos fármacos
Eritrócitos/citologia
Eritrócitos/efeitos dos fármacos
Citometria de Fluxo
Hemólise
Seres Humanos
Indóis/farmacologia
Cinética
Lisofosfolipídeos/farmacologia
Maleimidas/farmacologia
Fosfatidilserinas/farmacologia
Proteína Quinase C-alfa/antagonistas & inibidores
Acetato de Tetradecanoilforbol/análogos & derivados
Acetato de Tetradecanoilforbol/farmacologia
Xantenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide); 0 (Agatoxins); 0 (Aniline Compounds); 0 (Calcium Channels, N-Type); 0 (Fluo 4); 0 (Indoles); 0 (Lysophospholipids); 0 (Maleimides); 0 (Phosphatidylserines); 0 (Xanthenes); 0 (omega-agatoxin-Aa4b); 0 (voltage-dependent calcium channel (P-Q type)); 57716-89-9 (4-O-methyl-12-O-tetradecanoylphorbol 13-acetate); EC 2.7.11.13 (Protein Kinase C-alpha); NI40JAQ945 (Tetradecanoylphorbol Acetate); PG6M3969SG (lysophosphatidic acid); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1402
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130703
[St] Status:MEDLINE
[do] DOI:10.1159/000350106


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[PMID]:23573262
[Au] Autor:Moore SJ; Leung CL; Norton HK; Cochran JR
[Ad] Endereço:Department of Bioengineering, Stanford University, Stanford, California, United States of America.
[Ti] Título:Engineering agatoxin, a cystine-knot peptide from spider venom, as a molecular probe for in vivo tumor imaging.
[So] Source:PLoS One;8(4):e60498, 2013.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cystine-knot miniproteins, also known as knottins, have shown great potential as molecular scaffolds for the development of targeted therapeutics and diagnostic agents. For this purpose, previous protein engineering efforts have focused on knottins based on the Ecballium elaterium trypsin inhibitor (EETI) from squash seeds, the Agouti-related protein (AgRP) neuropeptide from mammals, or the Kalata B1 uterotonic peptide from plants. Here, we demonstrate that Agatoxin (AgTx), an ion channel inhibitor found in spider venom, can be used as a molecular scaffold to engineer knottins that bind with high-affinity to a tumor-associated integrin receptor. METHODOLOGY/PRINCIPAL FINDINGS: We used a rational loop-grafting approach to engineer AgTx variants that bound to αvß3 integrin with affinities in the low nM range. We showed that a disulfide-constrained loop from AgRP, a structurally-related knottin, can be substituted into AgTx to confer its high affinity binding properties. In parallel, we identified amino acid mutations required for efficient in vitro folding of engineered integrin-binding AgTx variants. Molecular imaging was used to evaluate in vivo tumor targeting and biodistribution of an engineered AgTx knottin compared to integrin-binding knottins based on AgRP and EETI. Knottin peptides were chemically synthesized and conjugated to a near-infrared fluorescent dye. Integrin-binding AgTx, AgRP, and EETI knottins all generated high tumor imaging contrast in U87MG glioblastoma xenograft models. Interestingly, EETI-based knottins generated significantly lower non-specific kidney imaging signals compared to AgTx and AgRP-based knottins. CONCLUSIONS/SIGNIFICANCE: In this study, we demonstrate that AgTx, a knottin from spider venom, can be engineered to bind with high affinity to a tumor-associated receptor target. This work validates AgTx as a viable molecular scaffold for protein engineering, and further demonstrates the promise of using tumor-targeting knottins as probes for in vivo molecular imaging.
[Mh] Termos MeSH primário: Agatoxinas
Neoplasias/diagnóstico
[Mh] Termos MeSH secundário: Agatoxinas/química
Agatoxinas/genética
Substituição de Aminoácidos
Animais
Carbocianinas/química
Cisteína/genética
Motivos Nó de Cisteína
Feminino
Corantes Fluorescentes/química
Seres Humanos
Integrina alfaVbeta3/metabolismo
Células K562
Camundongos
Camundongos Nus
Mutagênese Sítio-Dirigida
Transplante de Neoplasias
Ligação Proteica
Engenharia de Proteínas
Dobramento de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Agatoxins); 0 (Carbocyanines); 0 (Fluorescent Dyes); 0 (Integrin alphaVbeta3); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130411
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0060498


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[PMID]:22819793
[Au] Autor:Pringos E; Crouzin N; Cavalier M; Guiramand J; Cohen-Solal C; Martinez J; Vignes M; Rolland V
[Ad] Endereço:UMR 5247, Institut des Biomolécules Max Mousseron, CNRS, Université Montpellier 1 & Université Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
[Ti] Título:Synthesis and characterization of a cyclooctapeptide analogue of ω-agatoxin IVB enhancing the activity of Cav2.1 calcium channels activity in cultured hippocampal neurons.
[So] Source:Neurochem Int;61(5):632-9, 2012 Oct.
[Is] ISSN:1872-9754
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The structure of the toxin ω-agatoxin IVB, extracted from the venom of funnel-web spider Agelenopsis aperta, is an important lead structure when considering the design of modulators of synaptic transmission which largely involves P/Q-type (CaV2.1) voltage gated calcium channels (VGCC) at central synapses. Focusing on the loop 2 of the ω-agatoxin IVB that seems to be the most preeminent interacting domain of the toxin with the CaV2.1 VGCC, cyclooctapeptides mimicking this loop were synthesized. While (14)Trp is essential for the binding of the neurotoxin to the CaV2.1 VGCC, the substitution of the (12)Cys for a glycidyl residue led to a cyclooctapeptide named EP14 able to enhance CaV2.1 VGCC-associated currents measured with patch-clamp recordings and to evoke ω-agatoxin IVA-sensitive intracellular Ca(2+) increase as measured by fura-2 spectrofluoroimaging. Furthermore, this cyclooctapeptide was able to potentiate spontaneous excitatory synaptic transmission in a network of cultured hippocampal neurons, consistent with the activation of presynaptic VGCC by EP14. In addition, this peptide did not affect cell survival measured with the MTT assay. Therefore, such new cyclopeptidic structures are potential good candidates for synthesis of new agents aimed at the restoration deficient excitatory synaptic transmission.
[Mh] Termos MeSH primário: Agatoxinas/síntese química
Canais de Cálcio Tipo N/metabolismo
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Animais
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Células Cultivadas
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos
Potenciais Pós-Sinápticos Excitadores/fisiologia
Hipocampo/citologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Agatoxins); 0 (Calcium Channels, N-Type); 0 (omega-agatoxin-Aa4b); 0 (voltage-dependent calcium channel (P-Q type))
[Em] Mês de entrada:1307
[Cu] Atualização por classe:121016
[Lr] Data última revisão:
121016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120724
[St] Status:MEDLINE


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[PMID]:22542190
[Au] Autor:Nakayama H; Miyazaki T; Kitamura K; Hashimoto K; Yanagawa Y; Obata K; Sakimura K; Watanabe M; Kano M
[Ad] Endereço:Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
[Ti] Título:GABAergic inhibition regulates developmental synapse elimination in the cerebellum.
[So] Source:Neuron;74(2):384-96, 2012 Apr 26.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here, we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, by conditional deletion of GAD67 from PCs and GABAergic interneurons or by pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABA(A) receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca2+ imaging data suggest that GABA(A) receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF-induced Ca2+ transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16.
[Mh] Termos MeSH primário: Cerebelo/citologia
Cerebelo/crescimento & desenvolvimento
Células de Purkinje/citologia
Sinapses/fisiologia
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Agatoxinas/farmacologia
Fatores Etários
Análise de Variância
Animais
Animais Recém-Nascidos
Bicuculina/farmacologia
Fenômenos Biofísicos/efeitos dos fármacos
Fenômenos Biofísicos/genética
Biofísica
Calbindinas
Cálcio/metabolismo
Canais de Cálcio/metabolismo
Cromonas/farmacologia
Citocromos c/farmacologia
Dendritos/ultraestrutura
Diazepam/farmacologia
Estimulação Elétrica
Antagonistas de Aminoácidos Excitatórios/farmacologia
Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos
Potenciais Pós-Sinápticos Excitadores/genética
Moduladores GABAérgicos/farmacologia
Antagonistas de Receptores de GABA-A/farmacologia
Regulação da Expressão Gênica no Desenvolvimento/genética
Regulação da Expressão Gênica no Desenvolvimento/fisiologia
Glutamato Descarboxilase/genética
Proteínas de Fluorescência Verde/genética
Técnicas In Vitro
Potenciais da Membrana/genética
Potenciais da Membrana/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Microscopia Confocal
Microscopia Eletrônica de Transmissão
Proteínas do Tecido Nervoso/metabolismo
Neurotoxinas/farmacologia
Técnicas de Patch-Clamp
Fosfolipase C beta/metabolismo
Proteína Quinase C/metabolismo
Células de Purkinje/fisiologia
Quinoxalinas/farmacologia
Receptores de Glutamato/metabolismo
Receptores de Glutamato Metabotrópico/metabolismo
Proteína G de Ligação ao Cálcio S100/metabolismo
Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester); 0 (Agatoxins); 0 (Calbindins); 0 (Calcium Channels); 0 (Chromones); 0 (Excitatory Amino Acid Antagonists); 0 (GABA Modulators); 0 (GABA-A Receptor Antagonists); 0 (Nerve Tissue Proteins); 0 (Neurotoxins); 0 (Quinoxalines); 0 (Receptors, Glutamate); 0 (Receptors, Metabotropic Glutamate); 0 (S100 Calcium Binding Protein G); 0 (Vesicular Inhibitory Amino Acid Transport Proteins); 0 (Viaat protein, mouse); 0 (enhanced green fluorescent protein); 0 (glutamate receptor delta 2); 0 (metabotropic glutamate receptor type 1); 118876-58-7 (2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline); 147336-22-9 (Green Fluorescent Proteins); 56-12-2 (gamma-Aminobutyric Acid); 9007-43-6 (Cytochromes c); EC 2.7.11.13 (Protein Kinase C); EC 3.1.4.11 (Phospholipase C beta); EC 3.1.4.11 (Plcb4 protein, mouse); EC 4.1.1.15 (Glutamate Decarboxylase); EC 4.1.1.15 (glutamate decarboxylase 1); Q3JTX2Q7TU (Diazepam); SY7Q814VUP (Calcium); Y37615DVKC (Bicuculline)
[Em] Mês de entrada:1206
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120501
[St] Status:MEDLINE
[do] DOI:10.1016/j.neuron.2012.02.032



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