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1.
Proc Natl Acad Sci U S A ; 117(13): 7447-7454, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32165542

RESUMO

Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to neurotransmission, as well as initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is up-regulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs, and noncanonical amino acid-mediated photocrosslinking. We demonstrate that BigDyn binding results in an ASIC1a closed resting conformation that is distinct from open and desensitized states induced by protons. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is primarily mediated through electrostatic interactions of basic amino acids in the BigDyn N terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the noncanonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn, and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Dinorfinas/metabolismo , Canais Iônicos Sensíveis a Ácido/genética , Animais , Animais Geneticamente Modificados , Sítios de Ligação , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Oócitos/metabolismo , Prótons , Xenopus laevis
2.
J Neurosci ; 40(7): 1427-1439, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31932417

RESUMO

Long-term memory (LTM) is stored as functional modifications of relevant neural circuits in the brain. A large body of evidence indicates that the initial establishment of such modifications through the process known as memory consolidation requires learning-dependent transcriptional activation and de novo protein synthesis. However, it remains poorly understood how the consolidated memory is maintained for a long period in the brain, despite constant turnover of molecular substrates. Using the Drosophila courtship conditioning assay of adult males as a memory paradigm, here, we show that in Drosophila, environmental light plays a critical role in LTM maintenance. LTM is impaired when flies are kept in constant darkness (DD) during the memory maintenance phase. Because light activates the brain neurons expressing the neuropeptide pigment-dispersing factor (Pdf), we examined the possible involvement of Pdf neurons in LTM maintenance. Temporal activation of Pdf neurons compensated for the DD-dependent LTM impairment, whereas temporal knockdown of Pdf during the memory maintenance phase impaired LTM in light/dark cycles. Furthermore, we demonstrated that the transcription factor cAMP response element-binding protein (CREB) is required in the memory center, namely, the mushroom bodies (MBs), for LTM maintenance, and Pdf signaling regulates light-dependent transcription via CREB. Our results demonstrate for the first time that universally available environmental light plays a critical role in LTM maintenance by activating the evolutionarily conserved memory modulator CREB in MBs via the Pdf signaling pathway.SIGNIFICANCE STATEMENT Temporary memory can be consolidated into long-term memory (LTM) through de novo protein synthesis and functional modifications of neuronal circuits in the brain. Once established, LTM requires continual maintenance so that it is kept for an extended period against molecular turnover and cellular reorganization that may disrupt memory traces. How is LTM maintained mechanistically? Despite the critical importance of LTM maintenance, its molecular and cellular underpinnings remain elusive. This study using Drosophila is significant because it revealed for the first time in any organism that universally available environmental light plays an essential role in LTM maintenance. Interestingly, light does so by activating the evolutionarily conserved transcription factor cAMP response element-binding protein via peptidergic signaling.


Assuntos
Drosophila melanogaster/efeitos da radiação , Luz , Consolidação da Memória/efeitos da radiação , Memória de Longo Prazo/efeitos da radiação , Animais , Ritmo Circadiano , Condicionamento Clássico , Corte , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Escuridão , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/efeitos da radiação , Genes Reporter , Masculino , Consolidação da Memória/fisiologia , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Corpos Pedunculados/efeitos da radiação , Neurônios/fisiologia , Neurônios/efeitos da radiação , Neuropeptídeos/biossíntese , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas-G/fisiologia , Privação do Sono , Transcrição Genética/fisiologia
3.
Science ; 367(6476): 436-440, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974253

RESUMO

The ability of the nervous system to sense cellular stress and coordinate protein homeostasis is essential for organismal health. Unfortunately, stress responses that mitigate disturbances in proteostasis, such as the unfolded protein response of the endoplasmic reticulum (UPRER), become defunct with age. In this work, we expressed the constitutively active UPRER transcription factor, XBP-1s, in a subset of astrocyte-like glia, which extended the life span in Caenorhabditis elegans Glial XBP-1s initiated a robust cell nonautonomous activation of the UPRER in distal cells and rendered animals more resistant to protein aggregation and chronic ER stress. Mutants deficient in neuropeptide processing and secretion suppressed glial cell nonautonomous induction of the UPRER and life-span extension. Thus, astrocyte-like glial cells play a role in regulating organismal ER stress resistance and longevity.


Assuntos
Caenorhabditis elegans/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Longevidade , Neuroglia/fisiologia , Neuropeptídeos/fisiologia , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Mutação , Agregados Proteicos/fisiologia , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia
4.
J Neurosci ; 40(11): 2296-2304, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-31992587

RESUMO

The formation of memory declines with advancing age. However, susceptibility to memory impairments depends on several factors, including the robustness of memory, the responsible neural circuits, and the internal state of aged individuals. How age-dependent changes in internal states and neural circuits affect memory formation remains unclear. Here, we show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which suppresses their high mortality rates during starvation. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. We found that aging enhanced the preference for nutritious sugar over non-nutritious sugar correlated with an age-dependent increase in the expression of Drosophila neuropeptide F, an ortholog of mammalian neuropeptide Y. Furthermore, a subset of dopaminergic neurons that signal the sweet taste of sugar decreases its function with aging, while a subset of dopaminergic neurons that signal the nutritional value of sugar maintains its function with age. Our results suggest that aging impairs the ability to form memories without survival benefits; however, the ability to form memories with survival benefits is maintained through age-dependent changes in the neural circuits and neuropeptides.SIGNIFICANCE STATEMENT The susceptibility to age-dependent memory impairments depends on the strength of the memory, changes in the responsible neurons, and internal states of aged individuals. How age-dependent changes in such internal states affect neural activity and memory formation remains unclear. We show in Drosophila melanogaster that aged flies of both sexes form robust appetitive memory conditioned with nutritious sugar, which has survival benefits for aged flies. In contrast, aging impairs the formation of appetitive memory conditioned with non-nutritious sugar that lacks survival benefits for the flies. Aging changes the neural circuits including dopamine neurons and neuropeptide F-expressing neurons, leading to the age-dependent impairment in memory with insufficient survival benefits and the preservation of the ability to form memory with survival benefits.


Assuntos
Envelhecimento/fisiologia , Drosophila melanogaster/fisiologia , Preferências Alimentares/fisiologia , Memória/fisiologia , Animais , Arabinose , Condicionamento Clássico/fisiologia , Açúcares da Dieta , Neurônios Dopaminérgicos/classificação , Neurônios Dopaminérgicos/fisiologia , Feminino , Aprendizagem/fisiologia , Masculino , Corpos Pedunculados/fisiologia , Neuropeptídeos/fisiologia , Valor Nutritivo , Olfato/fisiologia , Sorbitol , Inanição/fisiopatologia , Sacarose , Sobrevida , Paladar/fisiologia
5.
Am J Physiol Endocrinol Metab ; 318(3): E330-E342, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846370

RESUMO

Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and liver kinase B1 during glucose starvation-dependent activation of AMPK. Here, we demonstrate that electrical pulse-stimulated (EPS) contraction of C2C12 myotubes or treadmill exercise of C57BL/6 mice enhanced reciprocal coimmunoprecipitation of Axin1 and AMPK from myotube lysates or gastrocnemius muscle tissue. Interestingly, EPS or exercise upregulated total cellular Axin1 levels in an AMPK-dependent manner in C2C12 myotubes and gastrocnemius mouse muscle, respectively. Also, direct activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide treatment of C2C12 myotubes or gastrocnemius muscle elevated Axin1 protein levels. On the other hand, siRNA-mediated Axin1 knockdown lessened activation of AMPK in contracted myotubes. Further, AMPK inhibition with compound C or siRNA-mediated knockdown of AMPK or Axin1 blocked contraction-induced GTP loading of Rac1, p21-activated kinase phosphorylation, and contraction-stimulated glucose uptake. In summary, our results suggest that an AMPK/Axin1-Rac1 signaling pathway mediates contraction-stimulated skeletal muscle glucose uptake.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Proteína Axina/fisiologia , Glucose/metabolismo , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Neuropeptídeos/fisiologia , Transdução de Sinais/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Proteína Axina/genética , Linhagem Celular , Estimulação Elétrica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/genética , Proteínas rac1 de Ligação ao GTP/genética
6.
Biol Aujourdhui ; 213(3-4): 81-86, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829929

RESUMO

This article focuses on the contributions made by Michel Jouvet about the neurons responsible for generating the muscle atonia of paradoxical sleep (REM sleep). He was the first to describe the neurons responsible for muscle atonia during paradoxical sleep using "pontine" cats (in which the forebrain has been removed down to the pons) and localized pontine lesions. Also discussed is the research going on in the 1980s, when Michel Jouvet was hunting for the hypnogenic factor. At that time, he thought that it was secreted by the hypophysis; but this factor finally turned out to be controlled by the hypocretin/orexin and melanin concentrating hormone neurones located in the lateral hypothalamus. Several unforgettable moments with Michel Jouvet are described which occurred between 1983 and his last moments with us.


Assuntos
Músculos/fisiologia , Neurologia/história , Neuropeptídeos/fisiologia , Sono REM/fisiologia , Animais , Gatos , França , História do Século XX , História do Século XXI , Humanos , Doenças Musculares/etiologia , Doenças Musculares/história , Narcolepsia/etiologia , Narcolepsia/história , Neurologia/tendências , Neuropeptídeos/história , Ratos
7.
Nat Neurosci ; 22(12): 2029-2039, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31659341

RESUMO

Motivational states modulate how animals value sensory stimuli and engage in goal-directed behaviors. The motivational states of thirst and hunger are represented in the brain by shared and unique neuromodulatory systems. However, it is unclear how such systems interact to coordinate the expression of appropriate state-specific behavior. We show that the activity of two brain neurons expressing leucokinin neuropeptide is elevated in thirsty and hungry flies, and that leucokinin release is necessary for state-dependent expression of water- and sugar-seeking memories. Leucokinin inhibits two types of mushroom-body-innervating dopaminergic neurons (DANs) to promote thirst-specific water memory expression, whereas it activates other mushroom-body-innervating DANs to facilitate hunger-dependent sugar memory expression. Selection of hunger- or thirst-appropriate memory emerges from competition between leucokinin and other neuromodulatory hunger signals at the level of the DANs. Therefore, coordinated modulation of the dopaminergic system allows flies to prioritize the expression of the relevant state-dependent motivated behavior.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Drosophila , Fome/fisiologia , Memória/fisiologia , Neuropeptídeos/fisiologia , Sede/fisiologia , Animais , Animais Endogâmicos , Comportamento Animal/fisiologia , Sinais (Psicologia) , Feminino , Privação de Alimentos/fisiologia , Masculino , Corpos Pedunculados/fisiologia , Inibição Neural/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Água , Privação de Água/fisiologia
8.
Int J Mol Sci ; 20(21)2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661900

RESUMO

The cholinergic efferent network from the medial septal nucleus to the hippocampus has an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to efficiently encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP) induces acetylcholine synthesis in medial septal nuclei. HCNP is processed from the N-terminal region of a 186 amino acid, 21 kD HCNP precursor protein called HCNP-pp (also known as Raf kinase inhibitory protein (RKIP) and phosphatidylethanolamine-binding protein 1 (PEBP1)). In this study, we generated HCNP-pp knockout (KO) mice and assessed their cholinergic septo-hippocampal projection, local field potentials in CA1, and behavioral phenotypes. No significant behavioral phenotype was observed in HCNP-pp KO mice. However, theta power in the CA1 of HCNP-pp KO mice was significantly reduced because of fewer cholineacetyltransferase-positive axons in the CA1 stratum oriens. These observations indicated disruption of cholinergic activity in the septo-hippocampal network. Our study demonstrates that HCNP may be a cholinergic regulator in the septo-hippocampal network.


Assuntos
Região CA1 Hipocampal/fisiologia , Neurônios Colinérgicos/fisiologia , Neuropeptídeos/fisiologia , Proteína de Ligação a Fosfatidiletanolamina/genética , Acetilcolina/metabolismo , Animais , Axônios/metabolismo , Escala de Avaliação Comportamental , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Colina O-Acetiltransferase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropeptídeos/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo
9.
Int Rev Neurobiol ; 147: 361-395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607361

RESUMO

A sedentary lifestyle is now known as a critical risk factor for accelerated aging-related neurodegenerative disorders. In contract, having regular physical exercise has opposite effects. Clinical findings have suggested that physical exercise can promote brain plasticity, particularly the hippocampus and the prefrontal cortex, that are important for learning and memory and mood regulations. However, the underlying mechanisms are still unclear. Animal studies reveal that the effects of physical exercise on promoting neuroplasticity could be mediated by different exerkines derived from the peripheral system and the brain itself. This book chapter summarizes the recent evidence from clinical and pre-clinical studies showing the emerging mediators for exercise-promoted brain health, including myokines secreted from skeletal muscles, adipokines from adipose tissues, and other factors secreted from the bone and liver.


Assuntos
Cognição/fisiologia , Exercício Físico/fisiologia , Plasticidade Neuronal/fisiologia , Neuropeptídeos/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Humanos
10.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426473

RESUMO

It is well known that emotions can interfere with the perception of physical pain, as well as with the development and maintenance of painful conditions. On the other hand, somatic pain can have significant consequences on an individual's affective behavior. Indeed, pain is defined as a complex and multidimensional experience, which includes both sensory and emotional components, thus exhibiting the features of a highly subjective experience. Over the years, neural pathways involved in the modulation of the different components of pain have been identified, indicating the existence of medial and lateral pain systems, which, respectively, project from medial or lateral thalamic nuclei to reach distinct cortex regions relating to specific functions. However, owing to the limited information concerning how mood state and painful input affect each other, pain treatment is frequently unsatisfactory. Different neuromodulators, including endogenous neuropeptides, appear to be involved in pain-related emotion and in its affective influence on pain perception, thus playing key roles in vulnerability and clinical outcome. Hence, this review article focuses on evidence concerning the modulation of the sensory and affective dimensions of pain, with particular attention given to some selected neuropeptidergic system contributions.


Assuntos
Emoções , Neuropeptídeos/fisiologia , Dor , Animais , Córtex Cerebral , Metilação de DNA , Epigênese Genética , Humanos , Vias Neurais
11.
Insect Biochem Mol Biol ; 114: 103229, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31449846

RESUMO

The natural colorful cuticles of insects play important roles in many physiological processes. Pigmentation is a physiological process with a complex regulatory network whose regulatory mechanism remains unclear. Bombyx mori pigmentation mutants are ideal materials for research on pigmentation mechanisms. The purple quail-like (q-lp) and brown quail-like (q-lb) mutants originated from plain silkworm breeds 932VR and 0223JH respectively exhibit similar cuticle pigmentation to that of the quail mutant. The q-lp mutant also presents a developmental abnormality. In this study, genes controlling q-lp and q-lb mutants were located on chromosome 8 by positional cloning. Then the neuropeptide gene orcokinin (OK) was identified to be the major gene responsible for two quail-like mutants. The B. mori orcokinin gene (BommoOK) produces two transcripts, BommoOKA and BommoOKB, by alternative splicing. The CRISPR/Cas9 system and orcokinin peptides injection were used for further functional verification. We show a novel function of BommoOKA in inhibiting pigmentation, and one mature peptide of orcokinin A, OKA_type2, is the key factor in pigmentation inhibition. These results provide a reference for studying the function of orcokinin and are of theoretical importance for studying the regulatory mechanism of pigmentation.


Assuntos
Bombyx/fisiologia , Neuropeptídeos/fisiologia , Pigmentação , Sequência de Aminoácidos , Animais , Sequência de Bases
12.
PLoS One ; 14(8): e0220496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31369617

RESUMO

The Rac1 and Rac3 GTPases are co-expressed in the developing nervous system, where they are involved in different aspects of neuronal development, including the formation of synapses. The deletion of both Rac genes determines a stronger reduction of dendritic spines in vitro compared to the knockout of either gene, indicating that Rac1 and Rac3 play a synergistic role in the formation of these structures. Here, we have addressed the role of each GTPase in the formation of dendritic spines by overexpressing either Rac1 or Rac3 in wildtype neurons, or by re-expressing either GTPase in double knockout hippocampal cultures. We show that the Rac3 protein is expressed with Rac1 in developing hippocampal neurons. Overexpression of either GTPase in WT neurons increases the density of dendritic spines, suggesting the involvement of both GTPases in their formation. We also found that the re-expression of either Rac1 or Rac3 in double knockout neurons is sufficient to restore spinogenesis. Rac1 is significantly more efficient than Rac3 in restoring the formation of spines. On the other hand the quantitative analysis in neurons overexpressing or re-expressing either GTPase shows that Rac3 induces a more pronounced increase in the size of the spines compared to Rac1. These enlarged spines form morphological synapses identified by the juxtaposition of postsynaptic and presynaptic markers. Thus, while Rac1 appears more efficient in inducing the formation of mature spines, Rac3 is more efficient in promoting their enlargement. Our study highlights specific roles of Rac1 and Rac3, which may be functionally relevant also to synaptic plasticity.


Assuntos
Espinhas Dendríticas/enzimologia , Hipocampo/citologia , Neurônios/enzimologia , Neuropeptídeos/fisiologia , Proteínas rac de Ligação ao GTP/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Animais , Espinhas Dendríticas/fisiologia , Imunofluorescência , Hipocampo/anatomia & histologia , Hipocampo/enzimologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Imagem com Lapso de Tempo
13.
PLoS One ; 14(7): e0219050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260470

RESUMO

Our previous study demonstrated that predominant feeding inhibitory effects were found in the crude extracts of foregut and midgut of the silkworm Bombyx mori larvae. To address the entero-intestinal control crucial for the regulation of insect feeding behavior, the present study identified and functionally characterized feeding inhibitory peptides from the midgut of B. mori larvae. Purification and structural analyses revealed that the predominant inhibitory factors in the crude extracts were allatotropin (AT) and GSRYamide after its C-terminal sequence. In situ hybridization revealed that AT and GSRYamide were expressed in enteroendocrine cells in the posterior and anterior midgut, respectively. Receptor screening using Ca2+-imaging technique showed that the B. mori neuropeptide G protein-coupled receptor (BNGR)-A19 and -A22 acted as GSRYamide receptors and BNGR-A5 acted as an additional AT receptor. Expression analyses of these receptors and the results of the peristaltic motion assay indicated that these peptides participated in the regulation of intestinal contraction. Exposure of pharynx and ileum to AT and GSRYamide inhibited spontaneous contraction in ad libitum-fed larvae, while exposure of pharynx to GSRYamide did not inhibit contraction in non-fed larvae, indicating that the feeding state changed their sensitivity to inhibitory peptides. These different responses corresponded to different expression levels of their receptors in the pharynx. In addition, injection of AT and GSRYamide decreased esophageal contraction frequencies in the melamine-treated transparent larvae. These findings strongly suggest that these peptides exert feeding inhibitory effects by modulating intestinal contraction in response to their feeding state transition, eventually causing feeding termination.


Assuntos
Bombyx/fisiologia , Comportamento Alimentar/fisiologia , Animais , Bombyx/citologia , Bombyx/genética , Células Enteroendócrinas/fisiologia , Genes de Insetos , Hormônios de Inseto/genética , Hormônios de Inseto/fisiologia , Proteínas de Insetos/genética , Proteínas de Insetos/fisiologia , Intestinos/citologia , Intestinos/fisiologia , Larva/genética , Larva/fisiologia , Modelos Biológicos , Contração Muscular/fisiologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Oligopeptídeos/genética , Oligopeptídeos/fisiologia , Filogenia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/fisiologia , Transdução de Sinais
14.
Biol Pharm Bull ; 42(9): 1605-1607, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243195

RESUMO

Recently, we demonstrated that Rac1 upregulation is involved in augmented bronchial smooth muscle (BSM) contractions of antigen-challenged mice. However, change in G protein-coupled receptor (GPCR)-induced Rac1 activation remains unknown in BSMs of repeatedly antigen-challenged (Chal.) mice. We here examined carbachol (CCh)-induced Rac1 activation in BSMs of Chal. mice. Gene expression levels of both Rac1 and Rac-guanine nucleotide exchange factors (GEFs), such as Tiam1 and Trio, were increased in BSMs of Chal. mice. Furthermore, CCh-induced Rac1 activation was inhibited by pretreatment with Rac1-GEF inhibitor NSC23766 and Rac1 inhibitor EHT1864 in BSMs of sensitized-control (S.C.) and Chal. mice. Compared with S.C. mice, CCh-induced Rac1 activation was increased in BSMs of Chal. mice. In conclusion, we reported that increased CCh-induced Rac1 activation via Tiam1 and Trio upregulation, in addition to upregulate Rac1, may be involved in increased CCh-induced BSM contractions in Chal. mice.


Assuntos
Brônquios/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Neuropeptídeos/fisiologia , Fosfoproteínas/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia , Aminoquinolinas/farmacologia , Animais , Antígenos , Asma/genética , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Carbacol , Fatores de Troca do Nucleotídeo Guanina/genética , Masculino , Camundongos Endogâmicos BALB C , Agonistas Muscarínicos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/genética , Ovalbumina , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Pirimidinas/farmacologia , Pironas/farmacologia , Quinolinas/farmacologia , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genética , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/genética
15.
Theriogenology ; 134: 121-128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167155

RESUMO

Metabolic hormones play essential regulatory roles in many biological processes, including morphogenesis, growth, and reproduction through the maintenance of energy balance. Various metabolic hormones originally discovered in mammals, including ghrelin, leptin, and nesfatin-1 have been identified and characterized in fish. However, physiological roles of these metabolic hormones in regulating reproduction are largely unknown in fishes, especially in males. While the information available is restricted, this review attempts to summarize the main findings on the roles of metabolic peptides on the reproductive system in male fishes with an emphasis on testicular development and spermatogenesis. Specifically, the primary goal is to review the physiological interactions between hormones that regulate reproduction and hormones that regulate metabolism as a critical determinant of testicular function. A brief introduction to the localization of metabolic hormones in fish testis is also provided. Besides, the consequences of fasting and food deprivation on testicular development and sperm quality will be discussed with a focus on interactions between metabolic and reproductive hormones.


Assuntos
Peixes/fisiologia , Hormônios/fisiologia , Espermatogênese , Animais , Grelina/metabolismo , Grelina/fisiologia , Hormônios/metabolismo , Leptina/metabolismo , Leptina/fisiologia , Masculino , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/fisiologia , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/fisiologia
16.
PLoS Genet ; 15(5): e1008176, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31150381

RESUMO

Gene expression changes in neural systems are essential for environment-induced behavioral plasticity in animals; however, neuronal signaling pathways mediating the effect of external stimuli on transcriptional changes are largely unknown. Recently, we have demonstrated that the neuropeptide F (NPF)/nitric oxide (NO) signaling pathway plays a regulatory role in phase-related locomotor plasticity in the migratory locust, Locusta migratoria. Here, we report that a conserved transcription factor, cAMP response element-binding protein B (CREB-B), is a key mediator involved in the signaling pathway from NPF2 to NOS in the migratory locust, triggering locomotor activity shift between solitarious and gregarious phases. We find that CREB-B directly activates brain NOS expression by interacting with NOS promoter region. The phosphorylation at serine 110 site of CREB-B dynamically changes in response to population density variation and is negatively controlled by NPF2. The involvement of CREB-B in NPF2-regulated locomotor plasticity is further validated by RNAi experiment and behavioral assay. Furthermore, we reveal that protein kinase A mediates the regulatory effects of NPF2 on CREB-B phosphorylation and NOS transcription. These findings highlight a precise signal cascade underlying environment-induced behavioral plasticity.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Locomoção/genética , Locusta migratoria/genética , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica/genética , Gafanhotos/genética , Gafanhotos/metabolismo , Locusta migratoria/metabolismo , Plasticidade Neuronal/genética , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Fosforilação , Regiões Promotoras Genéticas/genética , Interferência de RNA , Serina/metabolismo , Transdução de Sinais
17.
J Zhejiang Univ Sci B ; 20(7): 541-549, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168968

RESUMO

The ability to maintain metabolic homeostasis is a key capability critical for the survival and well-being of animals living in constantly changing environments. Metabolic homeostasis depends on neuromodulators, such as biogenic amines, neuropeptides, and hormones, to signal changes in animals' internal metabolic status and to orchestrate their behaviors accordingly. An important example is the regulation of feeding behavior by conserved molecular and cellular mechanisms across the animal kingdom. Its relatively simple brain coupled with well-characterized genetics and behavioral paradigms makes the fruit fly Drosophila melanogaster an excellent model for investigating the neuromodulatory regulation of feeding behavior. In this review we discuss the neuromodulators and neural circuits that integrate the internal physiological status with external sensory cues and modulate feeding behavior in adult fruit flies. Studies show that various specific aspects of feeding behavior are subjected to unique neuromodulatory regulation, which permits fruit flies to maintain metabolic homeostasis effectively.


Assuntos
Comportamento Animal , Drosophila melanogaster/fisiologia , Comportamento Alimentar , Neuropeptídeos/fisiologia , Neurotransmissores/fisiologia , Ciências da Nutrição Animal , Animais , Encéfalo/fisiologia , Feminino , Homeostase , Masculino , Motivação , Neurociências/tendências
18.
Ann Anat ; 225: 28-32, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195095

RESUMO

Anterior cruciate ligament (ACL) tears is a devastating injury and one of the most common knee injuries experienced by athletes in the United States. Although patients reach maximal subjective improvement by one-year following ACL reconstruction, many patients often experience moderate to severe post-operative pain. Opioids, intra-articular injections, and regional anesthesia have been previously implemented to mediate post-operative pain. However, chronic opioid usage has become an epidemic in the United States. Alternative analgesic modalities, such as nerve blocks, have been implemented in clinical practice to provide adequate pain relief and minimize opioid usage. Periarticular injections targeted towards local neurological structures performed concomitantly with nerve blocks provides superior pain relief and satisfaction than isolated nerve blocks. Therefore, it is imperative for physicians to understand local neurological anatomy around the knee joint in order to provide adequate analgesia while minimizing opioid consumption. This purpose of this investigation is to summarize (1) neurogenic origins of pain generators and mediators in sites affected by ACL reconstruction and autograft harvest sites and (2) analgesia utilized in ACL reconstruction.


Assuntos
Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/anatomia & histologia , Articulação do Joelho/irrigação sanguínea , Articulação do Joelho/inervação , Dor Pós-Operatória/etiologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestesia Local , Anestésicos Locais/administração & dosagem , Ligamento Cruzado Anterior/inervação , Ligamento Cruzado Anterior/cirurgia , Autoenxertos , Canais Iônicos/metabolismo , Mecanorreceptores/fisiologia , Bloqueio Nervoso , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Nociceptividade/fisiologia , Nociceptores/fisiologia
19.
Clin Rheumatol ; 38(7): 1889-1895, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127464

RESUMO

To report the simultaneous occurrence of psoriatic arthritis (PsA) and chronic regional pain syndrome type I (CRPS I) both triggered by intense walking in a male golfer with a history of scalp psoriasis. Sequential existence of these two conditions have been reported in the literature; however, to our knowledge, this is the first report of a simultaneous occurrence of PsA and CRPS I. This case illustrates the complex interplay between genetic predisposition and environmental risk factors with the central nervous and immune systems. As the pathogenesis of PsA has been better understood in recent years, we propose a mechanism that explains how the release of pro-inflammatory cytokines and neuropeptides following a traumatic event elicits a vicious cycle that is a common ground for the development of both PsA and CRPS I. Even unperceived trauma, such as intense walking, when directed to the synovio-entheseal complex, can precipitate the development of PsA and CRPS I in predisposed individuals.


Assuntos
Artrite Psoriásica/diagnóstico , Artrite Psoriásica/etiologia , Síndromes da Dor Regional Complexa/diagnóstico , Síndromes da Dor Regional Complexa/etiologia , Traumatismos do Pé/complicações , Doença Crônica , Citocinas/fisiologia , Traumatismos do Pé/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neuropeptídeos/fisiologia
20.
Am J Physiol Endocrinol Metab ; 317(1): E147-E157, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31084498

RESUMO

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Glucose/metabolismo , Hiperglicemia/metabolismo , Neuropeptídeos/farmacologia , Obesidade/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Células Cultivadas , Teste de Tolerância a Glucose , Homeostase/efeitos dos fármacos , Humanos , Hiperglicemia/complicações , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neuropeptídeos/fisiologia , Obesidade/complicações
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