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1.
J Physiol ; 595(18): 6121-6145, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28734079

RESUMO

KEY POINTS: Calcium homeostasis modulator 1 (CALHM1), a new voltage-gated ATP- and Ca2+ -permeable channel, plays important physiological roles in taste perception and memory formation. Regulatory mechanisms of CALHM1 remain unexplored, although the biophysical disparity between CALHM1 gating in vivo and in vitro suggests that there are undiscovered regulatory mechanisms. Here we report that CALHM1 gating and association with lipid microdomains are post-translationally regulated through the process of protein S-palmitoylation, a reversible attachment of palmitate to cysteine residues. Our data also establish cysteine residues and enzymes responsible for CALHM1 palmitoylation. CALHM1 regulation by palmitoylation provides new mechanistic insights into fine-tuning of CALHM1 gating in vivo and suggests a potential layer of regulation in taste and memory. ABSTRACT: Emerging roles of CALHM1, a recently discovered voltage-gated ion channel, include purinergic neurotransmission of tastes in taste buds and memory formation in the brain, highlighting its physiological importance. However, the regulatory mechanisms of the CALHM1 channel remain entirely unexplored, hindering full understanding of its contribution in vivo. The different gating properties of CALHM1 in vivo and in vitro suggest undiscovered regulatory mechanisms. Here, in searching for post-translational regulatory mechanisms, we discovered the regulation of CALHM1 gating and association with lipid microdomains via protein S-palmitoylation, the only reversible lipid modification of proteins on cysteine residues. CALHM1 is palmitoylated at two intracellular cysteines located in the juxtamembrane regions of the third and fourth transmembrane domains. Enzymes that catalyse CALHM1 palmitoylation were identified by screening 23 members of the DHHC protein acyltransferase family. Epitope tagging of endogenous CALHM1 proteins in mice revealed that CALHM1 is basally palmitoylated in taste buds in vivo. Functionally, palmitoylation downregulates CALHM1 without effects on its synthesis, degradation and cell surface expression. Mutation of the palmitoylation sites has a profound impact on CALHM1 gating, shifting the conductance-voltage relationship to more negative voltages and accelerating the activation kinetics. The same mutation also reduces CALHM1 association with detergent-resistant membranes. Our results comprehensively uncover a post-translational regulation of the voltage-dependent gating of CALHM1 by palmitoylation.


Assuntos
Canais de Cálcio/metabolismo , Ativação do Canal Iônico , Microdomínios da Membrana/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Canais de Cálcio/genética , Células HeLa , Humanos , Lipoilação , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Xenopus
2.
J Neurosci ; 36(24): 6431-44, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27307232

RESUMO

UNLABELLED: Postsynaptic density (PSD)-95, the most abundant postsynaptic scaffolding protein, plays a pivotal role in synapse development and function. Continuous palmitoylation cycles on PSD-95 are essential for its synaptic clustering and regulation of AMPA receptor function. However, molecular mechanisms for palmitate cycling on PSD-95 remain incompletely understood, as PSD-95 depalmitoylating enzymes remain unknown. Here, we isolated 38 mouse or rat serine hydrolases and found that a subset specifically depalmitoylated PSD-95 in heterologous cells. These enzymes showed distinct substrate specificity. α/ß-Hydrolase domain-containing protein 17 members (ABHD17A, 17B, and 17C), showing the strongest depalmitoylating activity to PSD-95, showed different localization from other candidates in rat hippocampal neurons, and were distributed to recycling endosomes, the dendritic plasma membrane, and the synaptic fraction. Expression of ABHD17 in neurons selectively reduced PSD-95 palmitoylation and synaptic clustering of PSD-95 and AMPA receptors. Furthermore, taking advantage of the acyl-PEGyl exchange gel shift (APEGS) method, we quantitatively monitored the palmitoylation stoichiometry and the depalmitoylation kinetics of representative synaptic proteins, PSD-95, GluA1, GluN2A, mGluR5, Gαq, and HRas. Unexpectedly, palmitate on all of them did not turn over in neurons. Uniquely, most of the PSD-95 population underwent rapid palmitoylation cycles, and palmitate cycling on PSD-95 decelerated accompanied by its increased stoichiometry as synapses developed, probably contributing to postsynaptic receptor consolidation. Finally, inhibition of ABHD17 expression dramatically delayed the kinetics of PSD-95 depalmitoylation. This study suggests that local palmitoylation machinery composed of synaptic DHHC palmitoylating enzymes and ABHD17 finely controls the amount of synaptic PSD-95 and synaptic function. SIGNIFICANCE STATEMENT: Protein palmitoylation, the most common lipid modification, dynamically regulates neuronal protein localization and function. Its unique reversibility is conferred by DHHC-type palmitoyl acyl transferases (palmitoylating enzymes) and still controversial palmitoyl-protein thioesterases (depalmitoylating enzymes). Here, we identified the membrane-anchored serine hydrolases, ABHD17A, 17B, and 17C, as the physiological PSD-95 depalmitoylating enzymes that regulate PSD-95 palmitoylation cycles in neurons. This study describes the first direct evidence for the neuronal depalmitoylating enzyme and provides a new aspect of the dynamic regulatory mechanisms of synaptic development and synaptic plasticity. In addition, our established APEGS assay, which provides unbiased and quantitative information about the palmitoylation state and dynamics, revealed the distinct regulatory mechanisms for synaptic palmitoylation.


Assuntos
Guanilato Quinases/metabolismo , Lipoilação/fisiologia , Proteínas de Membrana/metabolismo , Monoacilglicerol Lipases/metabolismo , Neurônios/enzimologia , Serina/análogos & derivados , Animais , Linhagem Celular Transformada , Cercopithecus aethiops , Cerebelo/metabolismo , Proteína 4 Homóloga a Disks-Large , Feminino , Guanilato Quinases/genética , Hipocampo/citologia , Hidrolases/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Monoacilglicerol Lipases/genética , Palmitatos/metabolismo , Transporte Proteico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Serina/isolamento & purificação , Serina/metabolismo , Frações Subcelulares/metabolismo , Especificidade por Substrato , Trítio/metabolismo
3.
Curr Top Membr ; 77: 97-141, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26781831

RESUMO

Palmitoylation is an evolutionally conserved lipid modification of proteins. Dynamic and reversible palmitoylation controls a wide range of molecular and cellular properties of proteins including the protein trafficking, protein function, protein stability, and specialized membrane domain organization. However, technical difficulties in (1) detection of palmitoylated substrate proteins and (2) purification and enzymology of palmitoylating enzymes have prevented the progress in palmitoylation research, compared with that in phosphorylation research. The recent development of proteomic and chemical biology techniques has unexpectedly expanded the known complement of palmitoylated proteins in various species and tissues/cells, and revealed the unique occurrence of palmitoylated proteins in membrane-bound organelles and specific membrane compartments. Furthermore, identification and characterization of DHHC (Asp-His-His-Cys) palmitoylating enzyme-substrate pairs have contributed to elucidating the regulatory mechanisms and pathophysiological significance of protein palmitoylation. Here, we review the recent progress in protein palmitoylation at the molecular, cellular, and in vivo level and discuss how locally regulated palmitoylation machinery works for dynamic nanoscale organization of membrane domains.


Assuntos
Lipoilação , Microdomínios da Membrana/metabolismo , Animais , Humanos , Espaço Intracelular/metabolismo , Proteínas/metabolismo
4.
Mol Biol Cell ; 26(12): 2333-42, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25904333

RESUMO

Adipocyte triglyceride lipase (ATGL) is the major enzyme involved in the hydrolysis of triglycerides. The Arf1-coat protein complex I (COPI) machinery is known to be engaged in the recruitment of ATGL to lipid droplets (LDs), but the regulatory mechanism has not been clarified. In the present study, we found that ELMOD2, a putative noncanonical Arf-GTPase activating protein (GAP) localizing in LDs, plays an important role in controlling ATGL transport to LDs. We showed that knockdown of ELMOD2 by RNA interference induced an increase in the amount of ATGL existing in LDs and decreased the total cellular triglycerides. These effects of ELMOD2 knockdown were canceled by transfection of small interfering RNA-resistant cDNA of wild-type ELMOD2 but not by that of mutated ELMOD2 lacking the Arf-GAP activity. ELMOD2 was distributed in the endoplasmic reticulum and mitochondria as well as in LDs, but palmitoylation was required only for distribution to LDs. An ELMOD2 mutant deficient in palmitoylation failed to reconstitute the ATGL transport after the ELMOD2 knockdown, indicating that distribution in LDs is indispensable to the functionality of ELMOD2. These results indicate that ELMOD2 regulates ATGL transport and cellular lipid metabolism by modulating the Arf1-COPI activity in LDs.


Assuntos
Adipócitos/metabolismo , Proteínas do Citoesqueleto/metabolismo , Lipase/metabolismo , Gotículas Lipídicas/metabolismo , Lipoilação , Fator 1 de Ribosilação do ADP/metabolismo , Adipócitos/enzimologia , Complexo I de Proteína do Envoltório/metabolismo , Regulação da Expressão Gênica , Humanos , Lipase/genética , Triglicerídeos/metabolismo
5.
Biochem Soc Trans ; 43(2): 199-204, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25849917

RESUMO

Precise regulation of protein assembly at specialized membrane domains is essential for diverse cellular functions including synaptic transmission. However, it is incompletely understood how protein clustering at the plasma membrane is initiated, maintained and controlled. Protein palmitoylation, a common post-translational modification, regulates protein targeting to the plasma membrane. Such modified proteins are enriched in these specialized membrane domains. In this review, we focus on palmitoylation of PSD-95, which is a major postsynaptic scaffolding protein and makes discrete postsynaptic nanodomains in a palmitoylation-dependent manner and discuss a determinant role of local palmitoylation cycles in creating highly localized hotspots at the membrane where specific proteins concentrate to organize functional domains.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipoilação/genética , Proteínas de Membrana/metabolismo , Transmissão Sináptica/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Proteína 4 Homóloga a Disks-Large , Hipocampo/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neurônios/metabolismo , Sinapses/genética , Sinapses/metabolismo
6.
Chemphyschem ; 16(9): 2015-20, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-25914350

RESUMO

The structure of FeOx species supported on γ-Al2 O3 was investigated by using Fe K-edge X-ray absorption fine structure (XAFS) and X-ray diffraction (XRD) measurements. The samples were prepared through the impregnation of iron nitrate on Al2 O3 and co-gelation of aluminum and iron sulfates. The dependence of the XRD patterns on Fe loading revealed the formation of α-Fe2 O3 particles at an Fe loading of above 10 wt %, whereas the formation of iron-oxide crystals was not observed at Fe loadings of less than 9.0 wt %. The Fe K-edge XAFS was characterized by a clear pre-edge peak, which indicated that the FeO coordination structure deviates from central symmetry and that the degree of FeOFe bond formation is significantly lower than that in bulk samples at low Fe loading (<9.0 wt %). Fe K-edge extended XAFS oscillations of the samples with low Fe loadings were explained by assuming an isolated iron-oxide monomer on the γ-Al2 O3 surface.

7.
J Clin Invest ; 125(4): 1497-508, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25751059

RESUMO

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.


Assuntos
Proteínas Angiogênicas/fisiologia , Guanilato Quinases/metabolismo , Hipocampo/fisiopatologia , Transtornos de Aprendizagem/genética , Proteínas de Membrana/metabolismo , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/fisiologia , Aprendizagem Espacial/fisiologia , Proteínas Angiogênicas/deficiência , Proteínas Angiogênicas/genética , Animais , Encéfalo/irrigação sanguínea , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases/deficiência , Guanilato Quinases/genética , Células HEK293 , Hipocampo/patologia , Humanos , Curva de Aprendizado , Transtornos de Aprendizagem/fisiopatologia , Potenciação de Longa Duração/fisiologia , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/ultraestrutura , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/metabolismo , Transmissão Sináptica/fisiologia , Ubiquitinação
8.
J Neurosci ; 35(11): 4776-87, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25788693

RESUMO

During brain development, Reelin exerts a variety of effects in a context-dependent manner, whereas its underlying molecular mechanisms remain poorly understood. We previously showed that the C-terminal region (CTR) of Reelin is required for efficient induction of phosphorylation of Dab1, an essential adaptor protein for canonical Reelin signaling. However, the physiological significance of the Reelin CTR in vivo remains unexplored. To dissect out Reelin functions, we made a knock-in (KI) mouse in which the Reelin CTR is deleted. The amount of Dab1, an indication of canonical Reelin signaling strength, is increased in the KI mouse, indicating that the CTR is necessary for efficient induction of Dab1 phosphorylation in vivo. Formation of layer structures during embryonic development is normal in the KI mouse. Intriguingly, the marginal zone (MZ) of the cerebral cortex becomes narrower at postnatal stages because upper-layer neurons invade the MZ and their apical dendrites are misoriented and poorly branched. Furthermore, Reelin undergoes proteolytic cleavage by proprotein convertases at a site located 6 residues from the C terminus, and it was suggested that this cleavage abrogates the Reelin binding to the neuronal cell membrane. Results from ectopic expression of mutant Reelin proteins in utero suggest that the dendrite development and maintenance of the MZ require Reelin protein with an intact CTR. These results provide a novel model regarding Reelin functions involving its CTR, which is not required for neuronal migration during embryonic stages but is required for the development and maintenance of the MZ in the postnatal cerebral cortex.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Animais , Células COS , Cercopithecus aethiops , Técnicas de Introdução de Genes/métodos , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos ICR , Proteólise
9.
Anim Sci J ; 83(12): 777-87, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23216543

RESUMO

Several studies have shown a relationship between depression and animal protein intake. To evaluate whether the difference of dietary chicken protein levels induces an antidepressant-like effect and potentiates acute antidepressant effects, three levels of dietary chicken protein were used as the representative animal protein with imipramine used as the antidepressant. In addition, the effects of dietary chicken protein on brain metabolism were evaluated. Open field test (OFT) and forced swimming test (FST) were conducted on the 27th and 28th days, respectively. OFT and FST were not influenced by both imipramine and dietary protein levels. However, characteristic effects of imipramine treatment on brain monoamine metabolism were observed in the cerebral cortex and hypothalamus. In addition, dietary protein significantly increased taurine and L-ornithine levels even though these amino acids were not contained in the diets. In conclusion, the metabolism of several amino acids in the plasma and brain were altered by dietary chicken protein.


Assuntos
Aminoácidos/metabolismo , Ração Animal , Antidepressivos Tricíclicos/farmacologia , Encéfalo/metabolismo , Proteínas na Dieta/administração & dosagem , Proteínas na Dieta/farmacologia , Imipramina/farmacologia , Produtos Avícolas , Aminoácidos/sangue , Animais , Monoaminas Biogênicas/metabolismo , Galinhas , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Ornitina/metabolismo , Taurina/metabolismo
10.
Anim Sci J ; 83(6): 493-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22694334

RESUMO

Several amino acids have effects on mental function, including sedative, antidepressant-like and anxiolytic-like effects. However, the influence of integrated amino acid nutrition as protein constituents on mental function remains unclear. Therefore, the purpose of the present study was to compare the influence of chicken, pork and beef protein extracts on brain monoamine metabolism in mice. Changes in monoamine levels and their turnover rates in the brain were induced by different protein sources. In particular, chicken protein group showed the highest norepinephrine levels in the hippocampus and hypothalamus, and beef protein extract caused an activation of the serotonergic system in the hypothalamus, although there were no significant differences in amino acid compositions of these protein extracts. Therefore, it was revealed that amino acid compositions in dietary protein did not induce alteration in monoamine metabolism. However, there were differences in small molecular peptides, such as creatine, carnosine and anserine levels in animal protein extracts. In conclusion, monoamine metabolism was altered by dietary protein sources. However, it was indicated that the alteration in monoamine metabolism may be independent from amino acid compositions in dietary protein. In addition, alteration in monoamine metabolism depending on the dietary protein sources may be induced by small molecular peptides.


Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Proteínas na Dieta/farmacologia , Carne , Aminoácidos/análise , Animais , Bovinos , Galinhas , Proteínas na Dieta/análise , Masculino , Camundongos , Camundongos Endogâmicos ICR , Peso Molecular , Peptídeos/análise , Suínos
11.
Nutr Neurosci ; 15(5): 26-33, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22643319

RESUMO

The relationship between antidepressants and monoamine concentrations in the brain has been well investigated, but few studies have investigated the relationship between antidepressants and amino acid concentrations in the brain. The purpose of the present study was therefore to investigate the effect of the chronic antidepressant imipramine on amino acid and monoamine concentrations in the mouse brain and plasma. Chronic imipramine treatment decreased the concentration of 5-hydroxyindoleaceticacid/5-hydroxytryptamine in the cerebral cortex and increased that of norepinephrine (NE) in the hippocampus. Since these changes were conspicuous effects of the antidepressant, we concluded that imipramine acts on the central nervous system. No change in amino acid concentrations in plasma was induced by chronic imipramine treatment, but several changes were confirmed in the cerebral cortex, the hypothalamus and the hippocampus. Chronic imipramine treatment caused increases in L-methionine, L-tyrosine, and L-lysine in the cerebral cortex, and an increase in L-aspartate in the hypothalamus. Contrary to this, the concentrations of L-aspartate, L-serine, L-asparagine, glycine, L-glutamine, gamma-aminobutyric acid, L-threonine, L-arginine, L-proline, L-valine, and L-methionine in the hippocampus were decreased by chronic imipramine treatment. The present results demonstrate that the metabolism of several amino acids in the brain, but not of those in plasma, was altered by chronic imipramine treatment. The findings in the present study may help to further elucidate the relationship between amino acids and the effects and side effects of antidepressants.


Assuntos
Aminoácidos/metabolismo , Antidepressivos Tricíclicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imipramina/farmacologia , Aminoácidos/sangue , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Relação Dose-Resposta a Droga , Ácido Hidroxi-Indolacético/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/metabolismo , Distribuição Aleatória , Serotonina/metabolismo
12.
Amino Acids ; 39(2): 427-34, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20099004

RESUMO

Taurine, a substrate of taurine transporter, has functions as a neuromodulator and antioxidant and beta-alanine, a taurine transporter inhibitor, has a role as a neurotransmitter in the brain, and they were expected to be involved in depression-like behavior and antidepressant treatment. These facts aroused our interest in new capabilities of taurine and beta-alanine. Thus, to investigate the effects of chronic ingestion of taurine- (22.5 mmol/kg diet) supplemented diet and beta-alanine- (22.5 mmol/kg diet) supplemented diet under acute stressful conditions, behavioral changes and brain metabolites were compared with mice fed a control diet. In the open field test, no significant difference was observed in locomotor activity among groups. In the elevated plus-maze test, however, significant increases in the percentage of time spent and entries in the open arms were observed in the beta-alanine-supplemented diet fed group compared to both controls and animals fed with taurine-supplemented diet. Moreover, a significant decrease in the duration of immobility was observed in the taurine-supplemented diet group in the forced swimming test compared to both controls and animals fed with beta-alanine-supplemented diet. Taurine-supplemented diet increased taurine and L: -arginine concentrations in the hypothalamus. In contrast, beta-alanine-supplemented diet decreased the concentration of 5-hydroxyindoleacetic acid, a major metabolite of serotonin, in the hypothalamus. Beta-alanine-supplemented diet also increased carnosine (beta-alanyl-L: -histidine) concentration in the cerebral cortex and hypothalamus, and brain-derived neurotrophic factor concentration in the hippocampus. These results suggested that taurine-supplemented diet had an antidepressant-like effect and beta-alanine-supplemented diet had an anxiolytic-like effect.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Taurina/farmacologia , beta-Alanina/farmacologia , Animais , Arginina/metabolismo , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carnosina/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Suplementos Nutricionais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Psicológico/tratamento farmacológico , Taurina/metabolismo
13.
Eur J Pharmacol ; 602(1): 73-7, 2009 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19010319

RESUMO

The relationships between monoamine metabolism and forced swimming or antidepressants have been well studied, however information is lacking regarding amino acid metabolism under these conditions. Therefore, the aim of the present study was to investigate the effects of forced swimming and imipramine on amino acid concentrations in plasma, the cerebral cortex and the hypothalamus in mice. Forced swimming caused cerebral cortex concentrations of L-glutamine, L-alanine, and taurine to be increased, while imipramine treatment caused decreased concentrations of L-glutamate, L-alanine, L-tyrosine, L-methionine, and L-ornithine. In the hypothalamus, forced swimming decreased the concentration of L-serine while imipramine treatment caused increased concentration of beta-alanine. Forced swimming caused increased plasma concentration of taurine, while concentrations of L-serine, L-asparagine, L-glutamine and beta-alanine were decreased. Imipramine treatment caused increased plasma concentration of all amino acid, except for L-aspartate and taurine. In conclusion, forced swimming and imipramine treatment modify central and peripheral amino acid metabolism. These results may aid in the identification of amino acids that have antidepressant-like effects, or may help to refine the dosages of antidepressant drugs.


Assuntos
Aminoácidos/sangue , Antidepressivos/farmacologia , Controle Comportamental , Química Encefálica/efeitos dos fármacos , Imipramina/farmacologia , Natação/fisiologia , Animais , Antidepressivos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Imipramina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR
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