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1.
PLoS Genet ; 16(6): e1008778, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32579604

RESUMO

Endurance exercise has broadly protective effects across organisms, increasing metabolic fitness and reducing incidence of several age-related diseases. Drosophila has emerged as a useful model for studying changes induced by chronic endurance exercise, as exercising flies experience improvements to various aspects of fitness at the cellular, organ and organismal level. The activity of octopaminergic neurons is sufficient to induce the conserved cellular and physiological changes seen following endurance training. All 4 octopamine receptors are required in at least one target tissue, but only one, Octß1R, is required for all of them. Here, we perform tissue- and adult-specific knockdown of alpha- and beta-adrenergic octopamine receptors in several target tissues. We find that reduced expression of Octß1R in adult muscles abolishes exercise-induced improvements in endurance, climbing speed, flight, cardiac performance and fat-body catabolism in male Drosophila. Importantly, Octß1R and OAMB expression in the heart is also required cell-nonautonomously for adaptations in other tissues, such as skeletal muscles in legs and adult fat body. These findings indicate that activation of distinct octopamine receptors in skeletal and cardiac muscle are required for Drosophila exercise adaptations, and suggest that cell non-autonomous factors downstream of octopaminergic activation play a key role.


Assuntos
Adaptação Fisiológica , Proteínas de Drosophila/metabolismo , Voo Animal , Coração/fisiologia , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neurotransmissores/metabolismo , Animais , Drosophila , Proteínas de Drosophila/genética , Corpo Adiposo/metabolismo , Músculo Esquelético/fisiologia , Receptores Acoplados a Proteínas-G/genética , Receptores de Neurotransmissores/genética
2.
Med Clin North Am ; 104(3): 439-454, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32312408

RESUMO

Anorexia and cachexia, nausea and vomiting, and constipation are gastrointestinal symptoms that commonly accompany serious illness. Basic science and clinical research continue to improve the understanding of their pathophysiology. Thorough assessment necessitates history, physical examination, and laboratory and diagnostic testing. Pharmacologic management attempts to counteract or reverse the underlying pathophysiologic mechanisms that accompany each symptom, which may benefit from a multimodal approach to achieve adequate control. Future improvements in management require investments in clinical research to determine the efficacy of novel agents along with comparator studies to better understand which treatments should be used in what sequence or combination.


Assuntos
Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Constipação Intestinal/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Anorexia/epidemiologia , Anorexia/fisiopatologia , Biomarcadores/metabolismo , Caquexia/epidemiologia , Caquexia/fisiopatologia , Terapia Combinada/métodos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/epidemiologia , Constipação Intestinal/fisiopatologia , Estado Terminal , Gastroenteropatias/epidemiologia , Gastroenteropatias/patologia , Gastroenteropatias/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Náusea/epidemiologia , Náusea/fisiopatologia , Cuidados Paliativos/métodos , Exame Físico/métodos , Exame Físico/normas , Qualidade de Vida/psicologia , Receptores de Neurotransmissores/efeitos dos fármacos , Vômito/epidemiologia
3.
FASEB J ; 34(1): 133-147, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914613

RESUMO

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes. NMU, which is synthesized in ß-cells and co-localizes with insulin, directly acts on ß-cells via NMU receptor 1 (NMUR1) to suppress glucose-stimulated insulin secretion (GSIS). The mechanism underlying this insulinostatic effect has yet to be elucidated. We observed that NMU caused mitochondrial dysfunction by impairing mitochondrial biogenesis, respiration, and mitochondrial Ca2+ uptake in ß-cell-derived MIN6-K8 cells. NMU administration induced the endoplasmic reticulum (ER) stress, as reflected by the activation of ER stress signaling pathways involving ATF6, XBP-1s, and PERK-ATF4-CHOP. Nmu knockdown in MIN6-K8 cells increased the number of insulin granules and improved mitochondrial biogenesis and function. NMU was upregulated in both the islets of db/db mice and palmitate-treated MIN6-K8 cells. Our results highlight the crucial role of NMU in the maintenance of ß-cell function and glucose metabolism through regulation of mitochondria dysfunction and ER stress. In pathological stages that develop into diabetes, upregulation of NMU could suppress the insulin secretion by inducing mitochondrial dysfunction and ER stress, which may contribute to subsequent ß-cell dysfunction.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Mitocôndrias/efeitos dos fármacos , Neuropeptídeos/farmacologia , Animais , Apoptose , Cálcio , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulinoma , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Interferência de RNA , Espécies Reativas de Oxigênio , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo
4.
Neuron ; 105(4): 663-677.e8, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31837915

RESUMO

A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.


Assuntos
Endocitose/fisiologia , Terminações Pré-Sinápticas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Vesículas Sinápticas/metabolismo , Analgésicos Opioides/farmacologia , Animais , Células Cultivadas , Endocitose/efeitos dos fármacos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/agonistas , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/metabolismo , Vesículas Sinápticas/efeitos dos fármacos
5.
Bull Exp Biol Med ; 168(2): 193-198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776959

RESUMO

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores de Neurotransmissores/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Animais , Colina/antagonistas & inibidores , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Ratos , Receptores Dopaminérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
6.
Nutrients ; 11(11)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31717954

RESUMO

We have previously shown that 6 weeks of intermittent high-fat diet (Int-HFD) pre-exposure significantly reduced alcohol drinking in rats, providing preliminary evidence of the effectiveness of a dietary intervention in reducing alcohol intake. However, the functional framework and underlying neurobiological mechanisms of such dietary intervention are unknown. Here, we examined the impact of Int-HFD pre-exposure duration on alcohol drinking, plasma feeding peptides, and central neurotransmitter receptors gene expression. Male Long Evans rats (n = 6-7/group) received no pre-exposure, 1 or 2 weeks pre-exposure to Int-HFD and alcohol drinking (two-bottle choice) was evaluated. We observed HFD pre-exposure-dependent decrease in alcohol drinking, with a significant decrease observed following 2 weeks of Int-HFD pre-exposure. No significant between-group differences in plasma feeding peptides (i.e., ghrelin, leptin, insulin) were detected. A PCR array revealed that the expression of several neurotransmitter receptors was significantly (p < 0.05 and ≥2-fold) altered in the striatum and ventral tegmental area compared to controls. These data suggest that pre-exposure to a palatable diet is critical to reduce alcohol drinking in rats, possibly through genetic alterations in the brain reward circuitry. Importantly, the present study is a step forward in identifying the critical framework needed to evaluate the therapeutic potential of nutritional contingency in the management of alcoholism.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Dieta Hiperlipídica , Receptores de Neurotransmissores/metabolismo , Animais , Peso Corporal , Gorduras na Dieta/metabolismo , Comportamento Alimentar , Masculino , Hormônios Peptídicos/metabolismo , Ratos , Ratos Long-Evans , Transcriptoma
7.
Yakugaku Zasshi ; 139(11): 1377-1384, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685733

RESUMO

Biomolecule-derived peptides are attractive research resources to develop drugs and elucidate the basic mechanisms of life phenomena. This review article focuses on two biomolecules called "neuromedin U (NMU)" and "myostatin" that are deeply involved in obesity and muscle weakness caused by modern lifestyles and aging. A structure-activity relationship (SAR) study based on a biomolecule reveals the structural features required for the biological activity and gives clues leading the drug discovery process. NMU activates two types of receptors (NMUR1 and NMUR2). NMU, which is an attractive candidate for treating obesity, displays a variety of physiological actions in addition to appetite suppression. The discovery of useful receptor-selective agonists helps in elucidating the detailed roles of the respective receptors for each action and in developing therapeutic drugs based on receptor function. Hence, SAR studies focused on the amidated C-terminal heptapeptide of NMU were carried out to obtain selective agonists. Consequently, the respective hexapeptidic NMUR1 and NMUR2 agonists CPN-267 and CPN-116 were discovered. Myostatin, an endogenous negative regulator of skeletal muscle mass, is a promising target for treating muscle atrophy disorders. Focused on the inactivation mechanism of mature myostatin by the myostatin precursor-derived prodomain, a core peptide (23-mer) for effective myostatin inhibition was identified from the mouse myostatin prodomain sequence. The SAR study based on this core peptide afforded a 25-fold more potent derivative (16-mer), which increased skeletal muscle mass and hindlimb grip strength. Therefore, this derivative could be a novel platform for a peptidic drug useful in the treatment of muscle atrophy.


Assuntos
Química Farmacêutica , Descoberta de Drogas , Miostatina/química , Neuropeptídeos/química , Peptídeos/química , Envelhecimento , Humanos , Estilo de Vida , Terapia de Alvo Molecular , Debilidade Muscular , Atrofia Muscular/terapia , Neuropeptídeos/uso terapêutico , Obesidade/tratamento farmacológico , Receptores de Neurotransmissores/agonistas , Relação Estrutura-Atividade
8.
Adv Exp Med Biol ; 1175: 45-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583584

RESUMO

Astrocytes are principal cells responsible for maintaining the brain homeostasis. Additionally, these glial cells are also involved in homocellular (astrocyte-astrocyte) and heterocellular (astrocyte-other cell types) signalling and metabolism. These astroglial functions require an expression of the assortment of molecules, be that transporters or pumps, to maintain ion concentration gradients across the plasmalemma and the membrane of the endoplasmic reticulum. Astrocytes sense and balance their neurochemical environment via variety of transmitter receptors and transporters. As they are electrically non-excitable, astrocytes display intracellular calcium and sodium fluctuations, which are not only used for operative signalling but can also affect metabolism. In this chapter we discuss the molecules that achieve ionic gradients and underlie astrocyte signalling.


Assuntos
Astrócitos/fisiologia , Encéfalo/fisiologia , Transdução de Sinais , Cálcio , Homeostase , Humanos , Bombas de Íon/fisiologia , Neuroglia , Receptores de Neurotransmissores/fisiologia , Sódio
9.
Pharmacol Rev ; 71(4): 520-538, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31530573

RESUMO

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in cis and trans Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and other neuropsychiatric disorders are significantly associated with mutations in neurogenic transcriptional networks. In this review, we have reanalyzed the results from publications of the PsychENCODE Consortium using pharmacoinformatics network analysis to better understand druggable targets that control neurogenic transcriptional networks. We found that valproic acid and other psychotropic drugs directly alter these networks, including chromatin remodeling complexes, transcription factors, and other epigenetic modifiers. We envision a new generation of CNS therapeutics targeted at neurogenic transcriptional control networks, including druggable parts of chromatin remodeling complexes and master transcription factor-controlled pharmacogenomic networks. This may provide a route to the modification of interconnected gene pathways impacted by disease in patients with neuropsychiatric and neurodegenerative disorders. Direct and indirect therapeutic strategies to modify the master regulators of neurogenic transcriptional control networks may ultimately help extend the life span of CNS neurons impacted by disease.


Assuntos
Redes Reguladoras de Genes/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Cromatina/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Genoma Humano/efeitos dos fármacos , Humanos , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Neuron ; 103(4): 563-581, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437453

RESUMO

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.


Assuntos
Plasticidade Neuronal/fisiologia , Neurotransmissores/fisiologia , Potenciais de Ação , Animais , Astrócitos/fisiologia , Comportamento/fisiologia , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Mapeamento Encefálico , Humanos , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Modelos Neurológicos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/fisiologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Terminações Pré-Sinápticas/fisiologia , Receptores de Neurotransmissores/fisiologia , Reforço Psicológico , Transdução de Sinais/fisiologia , Especificidade da Espécie , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Fatores de Tempo
11.
BMC Genomics ; 20(1): 677, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31455240

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells. RESULTS: Here, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α). CONCLUSIONS: These findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Encéfalo/metabolismo , Janus Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Encéfalo/enzimologia , Células Cultivadas , Proteínas Cromossômicas não Histona/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Canais Iônicos/biossíntese , Canais Iônicos/genética , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , RNA-Seq , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/biossíntese , Receptores de Neurotransmissores/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais , Transcriptoma
12.
Cell Host Microbe ; 26(2): 273-282.e7, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31378678

RESUMO

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.


Assuntos
Bactérias/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota/imunologia , Microbiota/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Proteínas Angiogênicas/agonistas , Animais , Cadaverina/metabolismo , Cadaverina/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Fermentação , Vida Livre de Germes , Agonistas dos Receptores Histamínicos , Humanos , Sistema Imunitário , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Propionatos/metabolismo , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Receptores de Neurotransmissores/agonistas
13.
Brain Struct Funct ; 224(8): 2733-2756, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31392403

RESUMO

The macaque monkey superior parietal lobule (SPL) is part of a neuronal network involved in the integration of information from visual and somatosensory cortical areas for execution of reaching and grasping movements. We applied quantitative in vitro receptor autoradiography to analyse the distribution patterns of 15 different receptors for glutamate, GABA, acetylcholine, serotonin, dopamine, and adenosine in the SPL of three adult male Macaca fascicularis monkeys. For each area, mean (averaged over all cortical layers) receptor densities were visualized as a receptor fingerprint of that area. Multivariate analyses were conducted to detect clusters of areas according to the degree of (dis)similarity of their receptor organization. Differences in regional and laminar receptor distributions confirm the location and extent of areas V6, V6Av, V6Ad, PEc, PEci, and PGm as found in cytoarchitectonic and functional studies, but also enable the definition of three subdivisions within area PE. Receptor densities are higher in supra- than in infragranular layers, with the exception of kainate, M2, and adenosine receptors. Glutamate and GABAergic receptors are the most expressed in all areas analysed. Hierarchical cluster analyses demonstrate that SPL areas are organized in two groups, an organization that corresponds to the visual or sensory-motor characteristics of those areas. Finally, based on present results and in the framework of our current understanding of the structural and functional organization of the primate SPL, we propose a novel pattern of homologies between human and macaque SPL areas.


Assuntos
Neurônios/citologia , Neurônios/metabolismo , Lobo Parietal/citologia , Lobo Parietal/metabolismo , Receptores de Neurotransmissores/metabolismo , Animais , Autorradiografia , Macaca fascicularis , Masculino , Receptores Colinérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores de Serotonina/metabolismo
15.
Cell Mol Neurobiol ; 39(8): 1071-1080, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31222426

RESUMO

Calcium signaling has essential roles in the development of the nervous system, from neural induction to the proliferation, migration, and differentiation of both neuronal and glia cells. The temporal and spatial dynamics of Ca2+ signals control the highly diverse yet specific transcriptional programs that establish the complex structures of the nervous system. Ca2+-signaling pathways are shaped by interactions among metabotropic signaling cascades, ion channels, intracellular Ca2+ stores, and a multitude of downstream effector proteins that activate specific genetic programs. Progress in the last decade has led to significant advances in our understanding of the functional architecture of Ca2+ signaling networks involved in oligodendrocyte development. In this review, we summarize the molecular and functional organizations of Ca2+-signaling networks during the differentiation of oligodendrocyte, especially its impact on myelin gene expression, proliferation, migration, and myelination. Importantly, the existence of multiple routes of Ca2+ influx opens the possibility that the activity of calcium channels can be manipulated pharmacologically to encourage oligodendrocyte maturation and remyelination after demyelinating episodes in the brain.


Assuntos
Sinalização do Cálcio , Oligodendroglia/metabolismo , Animais , Axônios/metabolismo , Canais de Cálcio/metabolismo , Humanos , Bainha de Mielina/metabolismo , Receptores de Neurotransmissores/metabolismo
16.
Nat Cell Biol ; 21(6): 721-730, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110287

RESUMO

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit ß-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine.


Assuntos
Células-Tronco Hematopoéticas/citologia , Receptores de Neurotransmissores/genética , Proteínas Wnt/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Receptores ErbB/genética , Humanos , Fosforilação , Via de Sinalização Wnt , Peixe-Zebra/crescimento & desenvolvimento , beta Catenina/genética
17.
Biomolecules ; 9(4)2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970612

RESUMO

Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). However, although it represents the "gold standard" of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.


Assuntos
Antiparkinsonianos/efeitos adversos , Levodopa/efeitos adversos , Neurotransmissores/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptores de Neurotransmissores/metabolismo , Animais , Antiparkinsonianos/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Humanos , Levodopa/uso terapêutico , Neurotransmissores/uso terapêutico , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores
18.
J Neuroimmunol ; 332: 99-111, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30999218

RESUMO

Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed.


Assuntos
Adenosina/metabolismo , Endocanabinoides/metabolismo , Endorfinas/metabolismo , Linfócitos/metabolismo , Neuroimunomodulação/fisiologia , Neurotransmissores/metabolismo , Animais , Medula Óssea/inervação , Encéfalo/fisiologia , Humanos , Tecido Linfoide/inervação , Neurônios/metabolismo , Nociceptividade/fisiologia , Receptores de Neurotransmissores/imunologia , Receptores de Neurotransmissores/metabolismo , Recompensa , Timo/inervação
19.
Gen Comp Endocrinol ; 280: 73-81, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981702

RESUMO

Evidence has shown that neuromedin S (NMS) and its receptor (NMU2R) are expressed in the hypothalamus, pituitary, and testis of pigs. To determine the potential mechanisms of NMS, we systematically investigated the direct effects of NMS on the hypothalamic-pituitary-testicular (HPT) axis of male pigs in vitro. We initially confirmed that NMU2R distributed in isolated hypothalamic cells, anterior pituitary cells and Leydig cells using immunocytochemistry. Subsequently we investigated the direct effects of NMS on hormone secretion from cells (anterior pituitary cells and Leydig cells) treated with different doses of NMS. The results showed that NMS increase the release of LH and FSH from anterior pituitary cells and testosterone from Leydig cells. NMS up-regulated the expression of NMU2R and GnRH mRNAs in hypothalamic cells, NMU2R, LH and FSH mRNAs in anterior pituitary cells, and NMU2R, STAR, P450 and 3ß-HSD mRNAs and the expression of PCNA and Cyclin B1 protein in Leydig cells; moreover, it down-regulated the expression of GnIH mRNA in hypothalamic cells. Using immunofluorescence staining and confocal microscopy, we also demonstrated the colocalization of NMU2R and AR or GnIH in Leydig cells. These data in vitro indicated that NMS may regulate the release and/or synthesis of LH, FSH and testosterone at different levels of the reproductive axis through NMU2R, which provided novel evidence of the potential roles of NMS in regulation of pig reproduction.


Assuntos
Hipotálamo/metabolismo , Neuropeptídeos/farmacologia , Hipófise/metabolismo , Testículo/metabolismo , Animais , Ciclina B1/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Hipófise/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Neurotransmissores/metabolismo , Suínos , Testículo/efeitos dos fármacos , Testosterona/metabolismo
20.
Dev Biol ; 452(1): 21-33, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029691

RESUMO

The asymmetric localization of planar cell polarity (PCP) proteins is essential for the establishment of many planar polarized cellular processes, but the mechanisms that maintain these asymmetric distributions remain poorly understood. A body of evidence has tied oriented subapical microtubules (MTs) to the establishment of PCP protein polarity, yet recent studies have suggested that the MT cytoskeleton is later dispensable for the maintenance of this asymmetry. As MTs underlie the vesicular trafficking of membrane-bound proteins within cells, the requirement for MTs in the maintenance of PCP merited further investigation. We investigated the complex interactions between PCP proteins and the MT cytoskeleton in the polarized context of the floorplate of the zebrafish neural tube. We demonstrated that the progressive posterior polarization of the primary cilia of floorplate cells requires not only Vangl2 but also Fzd3a. We determined that GFP-Vangl2 asymmetrically localizes to anterior membranes whereas Fzd3a-GFP does not polarize on anterior or posterior membranes but maintains a cytosolic enrichment at the base of the primary cilium. Vesicular Fzd3a-GFP is rapidly trafficked along MTs primarily toward the apical membrane during a period of PCP maintenance, whereas vesicular GFP-Vangl2 is less frequently observed. Nocodazole-induced loss of MT polymerization disrupts basal body positioning as well as GFP-Vangl2 localization and reduces cytosolic Fzd3a-GFP movements. Removal of nocodazole after MT disruption restores MT polymerization but does not restore basal body polarity. Interestingly, GFP-Vangl2 repolarizes to anterior membranes and vesicular Fzd3a-GFP dynamics recover after multiple hours of recovery, even in the context of unpolarized basal bodies. Together our findings challenge previous work by revealing an ongoing role for MT-dependent transport of PCP proteins in maintaining both cellular and PCP protein asymmetry during development.


Assuntos
Polaridade Celular , Cílios/metabolismo , Proteínas de Membrana/metabolismo , Microtúbulos/metabolismo , Receptores de Neurotransmissores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Cílios/genética , Proteínas de Membrana/genética , Microtúbulos/genética , Transporte Proteico , Receptores de Neurotransmissores/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
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