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Pesquisa : D12.776.157.530.562 [Categoria DeCS]
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[PMID]:27799294
[Au] Autor:Eshleman AJ; Wolfrum KM; Reed JF; Kim SO; Swanson T; Johnson RA; Janowsky A
[Ad] Endereço:Research Service, Portland VA Health Care System (A.J.E., K.M.W., J.F.R., S.O.K., T.S., R.A.J., A.J.), Departments of Psychiatry and Behavioral Neuroscience (A.J.E., A.J.), and Methamphetamine Abuse Research Center (T.S., A.J.), Oregon Health and Science University, Portland, Oregon eshleman@ohsu.ed
[Ti] Título:Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release.
[So] Source:J Pharmacol Exp Ther;360(1):33-47, 2017 Jan.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Synthetic cathinones are components of "bath salts" and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (K values) at radioligand binding sites, with relative affinities of hDAT>hNET>hSERT for α-pyrrolidinopropiophenone (α-PPP), α-pyrrolidinobutiophenone, α-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-α-pyrrolidinopropiophenone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 4-methyl-α-pyrrolidinopropiophenone, α-pyrrolidinovalerophenone, 4-methoxy-α-pyrrolidinovalerophenone, α-pyrrolidinopentiothiophenone (alpha-PVT), and α-methylaminovalerophenone, and hDAT>hSERT>hNET for methylenedioxypentedrone. Increasing the α-carbon chain length increased the affinity and potency of the α-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT>hNET>hSERT except α-PPP and α-PVT, which had highest potencies at hNET. They did not induce [ H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloro-methcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-N-ethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [ H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus K /IC ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity.
[Mh] Termos MeSH primário: Alcaloides/química
Alcaloides/farmacologia
Neurotransmissores/metabolismo
Neurotransmissores/secreção
Proteínas de Transporte de Neurotransmissores/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico/efeitos dos fármacos
Seres Humanos
Ligação Proteica/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Neurotransmitter Agents); 0 (Neurotransmitter Transport Proteins); 540EI4406J (cathinone)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161102
[St] Status:MEDLINE


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[PMID]:27835643
[Au] Autor:Sohail A; Jayaraman K; Venkatesan S; Gotfryd K; Daerr M; Gether U; Loland CJ; Wanner KT; Freissmuth M; Sitte HH; Sandtner W; Stockner T
[Ad] Endereço:Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.
[Ti] Título:The Environment Shapes the Inner Vestibule of LeuT.
[So] Source:PLoS Comput Biol;12(11):e1005197, 2016 Nov.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human neurotransmitter transporters are found in the nervous system terminating synaptic signals by rapid removal of neurotransmitter molecules from the synaptic cleft. The homologous transporter LeuT, found in Aquifex aeolicus, was crystallized in different conformations. Here, we investigated the inward-open state of LeuT. We compared LeuT in membranes and micelles using molecular dynamics simulations and lanthanide-based resonance energy transfer (LRET). Simulations of micelle-solubilized LeuT revealed a stable and widely open inward-facing conformation. However, this conformation was unstable in a membrane environment. The helix dipole and the charged amino acid of the first transmembrane helix (TM1A) partitioned out of the hydrophobic membrane core. Free energy calculations showed that movement of TM1A by 0.30 nm was driven by a free energy difference of ~15 kJ/mol. Distance measurements by LRET showed TM1A movements, consistent with the simulations, confirming a substantially different inward-open conformation in lipid bilayer from that inferred from the crystal structure.
[Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos/química
Sistemas de Transporte de Aminoácidos/ultraestrutura
Proteínas de Bactérias/química
Bicamadas Lipídicas/química
Proteínas de Transporte de Neurotransmissores/química
Proteínas de Transporte de Neurotransmissores/ultraestrutura
[Mh] Termos MeSH secundário: Proteínas de Bactérias/ultraestrutura
Modelos Químicos
Simulação de Dinâmica Molecular
Conformação Proteica
Domínios Proteicos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport Systems); 0 (Bacterial Proteins); 0 (Lipid Bilayers); 0 (Neurotransmitter Transport Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170530
[Lr] Data última revisão:
170530
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005197


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[PMID]:27591044
[Au] Autor:Bermingham DP; Blakely RD
[Ad] Endereço:Department of Pharmacology (D.P.B., R.D.B.) and Psychiatry (R.D.B.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Biomedical Sciences, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida (R.D.B.).
[Ti] Título:Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters.
[So] Source:Pharmacol Rev;68(4):888-953, 2016 10.
[Is] ISSN:1521-0081
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and disruption of clearance and reuptake has significant effects on physiology and behavior and has been linked to a number of neuropsychiatric disorders. To ensure adequate and dynamic control of these transporters, multiple modes of control have evolved to regulate their activity and trafficking. Central to many of these modes of control are the actions of protein kinases, whose actions can be direct or indirectly mediated by kinase-modulated protein interactions. Here, we summarize the current state of our understanding of how protein kinases regulate monoamine transporters through changes in activity, trafficking, phosphorylation state, and interacting partners. We highlight genetic, biochemical, and pharmacological evidence for kinase-linked control of DAT, NET, and SERT and, where applicable, provide evidence for endogenous activators of these pathways. We hope our discussion can lead to a more nuanced and integrated understanding of how neurotransmitter transporters are controlled and may contribute to disorders that feature perturbed monoamine signaling, with an ultimate goal of developing better therapeutic strategies.
[Mh] Termos MeSH primário: Proteínas de Transporte de Neurotransmissores/metabolismo
Proteínas Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Neurotransmitter Transport Proteins); EC 2.7.- (Protein Kinases)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171001
[Lr] Data última revisão:
171001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160904
[St] Status:MEDLINE
[do] DOI:10.1124/pr.115.012260


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[PMID]:27565422
[Au] Autor:Romei C; Bonifacino T; Milanese M; Usai C; Raiteri L
[Ad] Endereço:Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
[Ti] Título:Colocalization of neurotransmitter transporters on the plasma membrane of the same nerve terminal may reflect cotransmission.
[So] Source:Brain Res Bull;127:100-110, 2016 Oct.
[Is] ISSN:1873-2747
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is increasing evidence for the neuronal coexistence of classical transmitters. Implications in favor of cotransmission have often been represented by the identification, in the same neuron, of the putative cotransmitters, their synthetic enzymes and/or their vesicular transporters. In contrast, coexpression of neurotransmitter transporters on the plasma membrane of the same nerve terminal, although a potentially important indication for cotransmission, has received poor attention. We here used preparations of isolated nerve endings to functionally identify transporters coexpressed on the plasma membrane of the same terminal, in order to verify if such transporter coexpression indeed exists in neuronal systems in which cotransmission has already been established or reasonably suspected through other technical approaches. We could observe that functional transporters for glycine and glutamate are coexpressed on nerve terminals in the cerebellum; transporters for dopamine and GABA coexist on striatal terminals; transporters for glycine and GABA, previously found to coexist as cotransmission markers on nerve terminals of spinal cord and cerebellum, are not coexpressed in neocortex and hippocampus, where cotransmission has not been proposed to occur; transporters for GABA, glycine and glutamate are colocalized on nerve terminals of the spinal cord. Confocal microscopy experiments were performed to substantiate functional data, highlighting the presence of the co-existing transporters under study on MAP-2 positive synaptosomes. It is concluded that investigating the colocalization of functional neurotransmitter transporters on the plasma membrane of nerve terminals can provide useful information on the possibility of cotransmission.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Neurônios/metabolismo
Proteínas de Transporte de Neurotransmissores/metabolismo
Sinapses/metabolismo
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Animais
Membrana Celular/efeitos dos fármacos
Cerebelo/citologia
Cerebelo/efeitos dos fármacos
Cerebelo/metabolismo
Córtex Cerebral/citologia
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/metabolismo
Corpo Estriado/citologia
Corpo Estriado/efeitos dos fármacos
Corpo Estriado/metabolismo
Hipocampo/citologia
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Masculino
Camundongos
Microscopia Confocal
Neurônios/citologia
Neurônios/efeitos dos fármacos
Neurotransmissores/metabolismo
Neurotransmissores/farmacologia
Medula Espinal/citologia
Medula Espinal/efeitos dos fármacos
Medula Espinal/metabolismo
Sinapses/efeitos dos fármacos
Transmissão Sináptica/efeitos dos fármacos
Sinaptossomos/efeitos dos fármacos
Sinaptossomos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Agents); 0 (Neurotransmitter Transport Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160828
[St] Status:MEDLINE


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[PMID]:27474737
[Au] Autor:Khelashvili G; Schmidt SG; Shi L; Javitch JA; Gether U; Loland CJ; Weinstein H
[Ad] Endereço:From the Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10065, gek2009@med.cornell.edu.
[Ti] Título:Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290.
[So] Source:J Biol Chem;291(38):19786-99, 2016 Sep 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ions play key mechanistic roles in the gating dynamics of neurotransmitter:sodium symporters (NSSs). In recent microsecond scale molecular dynamics simulations of a complete model of the dopamine transporter, a NSS protein, we observed a partitioning of K(+) ions from the intracellular side toward the unoccupied Na2 site of dopamine transporter following the release of the Na2-bound Na(+) Here we evaluate with computational simulations and experimental measurements of ion affinities under corresponding conditions, the consequences of K(+) binding in the Na2 site of LeuT, a bacterial homolog of NSS, when both Na(+) ions and substrate have left, and the transporter prepares for a new cycle. We compare the results with the consequences of binding Na(+) in the same apo system. Analysis of >50-µs atomistic molecular dynamics and enhanced sampling trajectories of constructs with Glu(290), either charged or neutral, point to the Glu(290) protonation state as a main determinant in the structural reconfiguration of the extracellular vestibule of LeuT in which a "water gate" opens through coordinated motions of residues Leu(25), Tyr(108), and Phe(253) The resulting water channel enables the binding/dissociation of the Na(+) and K(+) ions that are prevalent, respectively, in the extracellular and intracellular environments.
[Mh] Termos MeSH primário: Bactérias/química
Proteínas de Bactérias/química
Proteínas de Transporte de Neurotransmissores/química
Potássio/química
Sódio/química
[Mh] Termos MeSH secundário: Animais
Bactérias/genética
Bactérias/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Cátions Monovalentes/química
Cátions Monovalentes/metabolismo
Proteínas de Drosophila/química
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Drosophila melanogaster
Ácido Glutâmico/química
Ácido Glutâmico/genética
Ácido Glutâmico/metabolismo
Proteínas de Transporte de Neurotransmissores/genética
Proteínas de Transporte de Neurotransmissores/metabolismo
Potássio/metabolismo
Estrutura Secundária de Proteína
Sódio/metabolismo
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Cations, Monovalent); 0 (Drosophila Proteins); 0 (Neurotransmitter Transport Proteins); 3KX376GY7L (Glutamic Acid); 9NEZ333N27 (Sodium); RWP5GA015D (Potassium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170916
[Lr] Data última revisão:
170916
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160731
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.731455


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[PMID]:27234819
[Au] Autor:Li Y; Zhang L; Sun Y; Ma X; Wang J; Li R; Zhang M; Wang S; Hu X; Bao Z
[Ad] Endereço:Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, China.
[Ti] Título:Transcriptome Sequencing and Comparative Analysis of Ovary and Testis Identifies Potential Key Sex-Related Genes and Pathways in Scallop Patinopecten yessoensis.
[So] Source:Mar Biotechnol (NY);18(4):453-65, 2016 Aug.
[Is] ISSN:1436-2236
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bivalve mollusks have fascinatingly diverse modes of reproduction. However, research investigating sex determination and reproductive regulation in this group of animals is still in its infancy. In this study, transcriptomes of three ovaries and three testes of Yesso scallop were sequenced and analyzed. Transcriptome comparison revealed that 4394 genes were significantly different between ovaries and testes, of which 1973 were ovary-biased (upregulated in the ovaries) and 2421 were testis-biased. Crucial sex-determining genes that were previously reported in vertebrates and putatively present in bivalves, namely FOXL2, DMRT, SOXH, and SOXE, were investigated. The genes all possessed conserved functional domains and were detected in the gonads. Except for PySOXE, the other three genes were significantly differentially expressed between the ovaries and testes. PyFOXL2 was ovary-biased, and PyDMRT and PySOXH were testis-biased, suggesting that these three genes are likely to be key candidates for scallop sex determination/differentiation. Furthermore, GO and KEGG enrichment analyses were conducted for both ovary- and testis-biased genes. Interestingly, both neurotransmitter transporters and GABAergic synapse genes were overrepresented in the ovary-biased genes, suggesting that neurotransmitters, such as GABA and glycine, are likely to participate in scallop ovary development. Our study will assist in better understanding of the molecular mechanisms underlying bivalve sex determination and reproductive regulation.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica no Desenvolvimento
Ovário/metabolismo
Pectinidae/genética
Processos de Determinação Sexual
Testículo/metabolismo
Transcriptoma
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Perfilação da Expressão Gênica
Ontologia Genética
Masculino
Anotação de Sequência Molecular
Proteínas de Transporte de Neurotransmissores/genética
Proteínas de Transporte de Neurotransmissores/metabolismo
Ovário/crescimento & desenvolvimento
Pectinidae/crescimento & desenvolvimento
Pectinidae/metabolismo
Receptores de GABA/genética
Receptores de GABA/metabolismo
Fatores de Transcrição SOXE/genética
Fatores de Transcrição SOXE/metabolismo
Alinhamento de Sequência
Análise de Sequência de DNA
Testículo/crescimento & desenvolvimento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Forkhead Transcription Factors); 0 (Neurotransmitter Transport Proteins); 0 (Receptors, GABA); 0 (SOXE Transcription Factors)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160529
[St] Status:MEDLINE
[do] DOI:10.1007/s10126-016-9706-8


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[PMID]:27036406
[Au] Autor:Pozdnyakova N; Pastukhov A; Dudarenko M; Galkin M; Borysov A; Borisova T
[Ad] Endereço:Department of Neurochemistry, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovicha Street, Kiev, 01601, Ukraine.
[Ti] Título:Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals.
[So] Source:J Nanobiotechnology;14:25, 2016 Mar 31.
[Is] ISSN:1477-3155
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nanodiamonds are one of the most perspective nano-sized particles with superb physical and chemical properties, which are mainly composed of carbon sp(3) structures in the core with sp(2) and disorder/defect carbons on the surface. The research team recently demonstrated neuromodulatory properties of carbon nanodots with other than nanodiamonds hybridization types, i.e., sp(2) hybridized graphene islands and diamond-like sp(3) hybridized elements. RESULTS: In this study, neuroactive properties of uncoated nanodiamonds produced by detonation synthesis were assessed basing on their effects on transporter-mediated uptake and the ambient level of excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), in isolated rat brain nerve terminals. It was shown that nanodiamonds in a dose-dependent manner attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake and accumulation of L-[(14)C]glutamate and [(3)H]GABA by nerve terminals and increased the ambient level of these neurotransmitters. Also, nanodiamonds caused a weak reduction in acidification of synaptic vesicles and depolarization of the plasma membrane of nerve terminals. CONCLUSIONS: Therefore, despite different types of hybridization in nanodiamonds and carbon dots, they exhibit very similar effects on glutamate and GABA transport in nerve terminals and this common feature of both nanoparticles is presumably associated with their nanoscale size. Observed neuroactive properties of pure nanodiamonds can be used in neurotheranostics for simultaneous labeling/visualization of nerve terminals and modulation of key processes of glutamate- and GABAergic neurotransmission. In comparison with carbon dots, wider medical application involving hypo/hyperthermia, external magnetic fields, and radiolabel techniques can be perspective for nanodiamonds.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Potenciais da Membrana/efeitos dos fármacos
Nanodiamantes/administração & dosagem
Terminações Nervosas/efeitos dos fármacos
Neurotransmissores/metabolismo
Proteínas de Transporte de Neurotransmissores/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Ácido Glutâmico/metabolismo
Masculino
Terminações Nervosas/metabolismo
Ratos
Ratos Wistar
Sódio/metabolismo
Vesículas Sinápticas/efeitos dos fármacos
Vesículas Sinápticas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nanodiamonds); 0 (Neurotransmitter Agents); 0 (Neurotransmitter Transport Proteins); 3KX376GY7L (Glutamic Acid); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160403
[St] Status:MEDLINE
[do] DOI:10.1186/s12951-016-0176-y


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[PMID]:26362361
[Au] Autor:Marusich JA; Antonazzo KR; Blough BE; Brandt SD; Kavanagh PV; Partilla JS; Baumann MH
[Ad] Endereço:Center for Drug Discovery, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709, USA. Electronic address: jmarusich@rti.org.
[Ti] Título:The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.
[So] Source:Neuropharmacology;101:68-75, 2016 Feb.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Indóis/farmacologia
Proteínas de Transporte de Neurotransmissores/metabolismo
[Mh] Termos MeSH secundário: Inibidores da Captação Adrenérgica/farmacologia
Animais
Estimulantes do Sistema Nervoso Central/farmacologia
Relação Dose-Resposta a Droga
Técnicas In Vitro
Masculino
Atividade Motora/efeitos dos fármacos
N-Metil-3,4-Metilenodioxianfetamina/farmacologia
Proteínas de Transporte de Neurotransmissores/genética
Ratos
Ratos Sprague-Dawley
Serotonina/farmacocinética
Fatores de Tempo
Trítio/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (5-(2-aminopropyl)indole); 0 (Adrenergic Uptake Inhibitors); 0 (Central Nervous System Stimulants); 0 (Indoles); 0 (Neurotransmitter Transport Proteins); 10028-17-8 (Tritium); 333DO1RDJY (Serotonin); KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150913
[St] Status:MEDLINE


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[PMID]:25920999
[Au] Autor:Nikishin DA; Milosevic I; Gojkovic M; Rakic L; Bezuglov VV; Shmukler YB
[Ad] Endereço:N.K. Koltzov Institute of Developmental Biology,Russian Academy of Sciences,Moscow,Russia.
[Ti] Título:Expression and functional activity of neurotransmitter system components in sea urchins' early development.
[So] Source:Zygote;24(2):206-18, 2016 Apr.
[Is] ISSN:1469-8730
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Reverse-transcription polymerase chain reaction (RT-PCR) investigation of the expression of the components supposedly taking part in serotonin regulation of the early development of Paracentrotus lividus has shown the presence of transcripts of five receptors, one of which has conservative amino acid residues characteristic of monoaminergic receptors. At the early stages of embryogenesis the expressions of serotonin transporter (SERT) and noradrenaline transporter (NET) were also recognized. The activities of the enzymes of serotonin synthesis and serotonin transporter were shown using immunohistochemistry and incubation with para-chlorophenylalanine (PСРА) and 5-hydroxytryptophan (HTP). Pharmacological experiments have shown a preferential cytostatic activity of ligands characterized as mammalian 5-hydroxytryptamine (5-HT)1-antagonists. On the basis of the sum of the data from molecular biology and embryo physiological experiments, it is suggested that metabotropic serotonin receptors and membrane transporters take part in the regulatory processes of early sea urchin embryogenesis.
[Mh] Termos MeSH primário: Arbacia/genética
Embrião não Mamífero/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Proteínas de Transporte de Neurotransmissores/genética
Paracentrotus/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Arbacia/embriologia
Arbacia/metabolismo
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo
Embrião não Mamífero/embriologia
Imuno-Histoquímica
Proteínas de Transporte de Neurotransmissores/metabolismo
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo
Paracentrotus/embriologia
Paracentrotus/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Homologia de Sequência de Aminoácidos
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Fatores de Tempo
Proteínas Vesiculares de Transporte de Monoamina/genética
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dopamine Plasma Membrane Transport Proteins); 0 (Neurotransmitter Transport Proteins); 0 (Norepinephrine Plasma Membrane Transport Proteins); 0 (Serotonin Plasma Membrane Transport Proteins); 0 (Vesicular Monoamine Transport Proteins)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150430
[St] Status:MEDLINE
[do] DOI:10.1017/S0967199415000040


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[PMID]:26116773
[Au] Autor:Chen R; Chung SH
[Ad] Endereço:Research School of Biology, Australian National University, Canberra, ACT 2601, Australia. Electronic address: rong.chen@anu.edu.au.
[Ti] Título:Molecular dynamics simulations of Na(+) and leucine transport by LeuT.
[So] Source:Biochem Biophys Res Commun;464(1):281-5, 2015 Aug 14.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Molecular dynamics simulations are used to gain insight into the binding of Na(+) and leucine substrate to the bacterial amino acid transporter LeuT, focusing on the crystal structures of LeuT in the outward-open and inward-open states. For both conformations of LeuT, a third Na(+) binding site involving Glu290 in addition to the two sites identified from the crystal structures is observed. Once the negative charge from Glu290 in the inward-open LeuT is removed, the ion bound to the third site is ejected from LeuT rapidly, suggesting that the protonation state of Glu290 regulates Na(+) binding and release. In Cl(-)-dependent transporters where Glu290 is replaced by a neutral serine, a Cl(-) ion would be required to replace the role of Glu290. Thus, the simulations provide insights into understanding Na(+) and substrate transport as well as Cl(-)-independence of LeuT.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Ácido Glutâmico/química
Leucina/química
Simulação de Dinâmica Molecular
Prótons
Sódio/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Transporte de Íons
Cinética
Proteínas de Transporte de Neurotransmissores/química
Ligação Proteica
Estrutura Secundária de Proteína
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Neurotransmitter Transport Proteins); 0 (Protons); 3KX376GY7L (Glutamic Acid); 9NEZ333N27 (Sodium); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:150721
[Lr] Data última revisão:
150721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150628
[St] Status:MEDLINE



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