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1.
J Neurosci ; 44(11)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38286627

RESUMO

Dopamine neurons play crucial roles in pleasure, reward, memory, learning, and fine motor skills and their dysfunction is associated with various neuropsychiatric diseases. Dopamine receptors are the main target of treatment for neurologic and psychiatric disorders. Antipsychotics that antagonize the dopamine D2 receptor (DRD2) are used to alleviate the symptoms of these disorders but may also sometimes cause disabling side effects such as parkinsonism (catalepsy in rodents). Here we show that GPR143, a G-protein-coupled receptor for L-3,4-dihydroxyphenylalanine (L-DOPA), expressed in striatal cholinergic interneurons enhances the DRD2-mediated side effects of haloperidol, an antipsychotic agent. Haloperidol-induced catalepsy was attenuated in male Gpr143 gene-deficient (Gpr143-/y ) mice compared with wild-type (Wt) mice. Reducing the endogenous release of L-DOPA and preventing interactions between GPR143 and DRD2 suppressed the haloperidol-induced catalepsy in Wt mice but not Gpr143-/y mice. The phenotypic defect in Gpr143-/y mice was mimicked in cholinergic interneuron-specific Gpr143-/y (Chat-cre;Gpr143flox/y ) mice. Administration of haloperidol increased the phosphorylation of ribosomal protein S6 at Ser240/244 in the dorsolateral striatum of Wt mice but not Chat-cre;Gpr143flox/y mice. In Chinese hamster ovary cells stably expressing DRD2, co-expression of GPR143 increased cell surface expression level of DRD2, and L-DOPA application further enhanced the DRD2 surface expression. Shorter pauses in cholinergic interneuron firing activity were observed after intrastriatal stimulation in striatal slice preparations from Chat-cre;Gpr143flox/y mice compared with those from Wt mice. Together, these findings provide evidence that GPR143 regulates DRD2 function in cholinergic interneurons and may be involved in parkinsonism induced by antipsychotic drugs.


Assuntos
Antipsicóticos , Transtornos Parkinsonianos , Receptores de Neurotransmissores , Humanos , Camundongos , Masculino , Animais , Cricetinae , Haloperidol/farmacologia , Levodopa/efeitos adversos , Catalepsia/induzido quimicamente , Células CHO , Cricetulus , Antipsicóticos/efeitos adversos , Interneurônios/metabolismo , Colinérgicos/farmacologia , Proteínas do Olho/metabolismo , Glicoproteínas de Membrana/metabolismo
2.
Cancer Sci ; 115(2): 334-346, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38071753

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, which is lethal in approximately 90% of cases despite advanced standard therapies. A typical feature of PDAC is the immunosuppressive tumor microenvironment with multiple immunosuppressive factors including neurotransmitters. Recently, neuromedin U (NMU), a highly conserved neuropeptide with many physiological functions, has attracted attention for its roles in tumorigenesis and metastasis in several types of cancers. However, whether NMU affects PDAC progression remains unclear. In this study, using an orthotopic mouse model of PDAC in combination with bioinformatics analysis, we found that NMU was upregulated in tumor tissues from the patients with PDAC and positively correlated with a poor prognosis of the disease. Interestingly, knockout of the Nmu gene in mice enhanced the anti-tumor functions of tumor-infiltrating CD8+ T cells in an NMU receptor 1-dependent manner. Additionally, NMU promoted the glycolytic metabolism of mouse PDAC tumors. The activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH), pivotal enzymes involved in the regulation of lactate production, were markedly reduced in tumor tissues from NMU-knockout mice. In vitro the presence of LDHA inhibitor can reduce the production of lactic acid stimulated by NMU, which can increase the anti-tumor activity of CD8+ T cells. Moreover, treatment of the pancreatic cancer cells with a phosphoinositide 3-kinase (PI3K) inhibitor diminished NMU-induced lactate production and the activities of PK and LDH, suggesting that NMU might regulate glycolysis via the PI3K/AKT pathway.


Assuntos
Carcinoma Ductal Pancreático , Neuropeptídeos , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/patologia , Linfócitos T CD8-Positivos/metabolismo , Glicólise , Lactatos , Neuropeptídeos/genética , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Microambiente Tumoral
3.
Cancer Res ; 83(23): 3868-3885, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-38037454

RESUMO

Nerves can support tumor development by secreting neurotransmitters that promote cancer cell proliferation and invasion. 5-Hydroxytryptamine (5-HT) is a critical neurotransmitter in the gastrointestinal nervous system, and 5-HT signaling has been shown to play a role in tumorigenesis. Here, we found that expression of the 5-HT receptor HTR2B was significantly elevated in human gastric adenocarcinoma tissues compared with nontumor tissues, and high HTR2B expression corresponded to shorter patient survival. Both 5-HT and a specific HTR2B agonist enhanced gastric adenocarcinoma cell viability under metabolic stress, reduced cellular and lipid reactive oxygen species, and suppressed ferroptosis; conversely, HTR2B loss or inhibition with a selective HTR2B antagonist yielded the inverse tumor suppressive effects. In a patient-derived xenograft tumor model, HTR2B-positive tumors displayed accelerated growth, which was inhibited by HTR2B antagonists. Single-cell analysis of human gastric adenocarcinoma tissues revealed enrichment of PI3K/Akt/mTOR and fatty acid metabolism-related gene clusters in cells expressing HTR2B compared with HTR2B-negative cells. Mechanistically, HTR2B cooperated with Fyn to directly regulate p85 activity and trigger the PI3K/Akt/mTOR signaling pathway, which led to increased expression of HIF1α and ABCD1 along with decreased levels of lipid peroxidation and ferroptosis. Together, these findings demonstrate that HTR2B activity modulates PI3K/Akt/mTOR signaling to stimulate gastric cancer cell survival and indicate that HTR2B expression could be a potential prognostic biomarker in patients with gastric cancer. SIGNIFICANCE: Nerve cancer cross-talk mediated by HTR2B inhibits lipid peroxidation and ferroptosis in gastric cancer cells and promotes viability under metabolic stress, resulting in increased tumor growth and decreased patient survival.


Assuntos
Adenocarcinoma , Ferroptose , Neoplasias Gástricas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Metabolismo dos Lipídeos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Neurotransmissores/metabolismo , Serotonina/metabolismo , Serotonina/farmacologia , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo
4.
Cell Rep ; 42(11): 113331, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37910506

RESUMO

Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.


Assuntos
Receptores de GABA-A , Sinapses , Sinapses/fisiologia , Proteínas de Transporte , Receptores de Neurotransmissores , Ácido gama-Aminobutírico
5.
Sci Rep ; 13(1): 18993, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37923782

RESUMO

Little is known about the expression of the orphan G protein-coupled receptor GPR19 at the protein level. Therefore, we developed a rabbit antibody, targeting human GPR19. After verification of the antibody specificity using GPR19-expressing cell lines and a GPR19-specific siRNA, the antibody was used for immunohistochemical staining of a variety of formalin-fixed, paraffin-embedded normal and neoplastic human tissue samples. In normal tissues, GPR19 expression was detected in a distinct cell population within the cortex, in single cells of the pancreatic islets, in intestinal ganglia, gastric chief cells, and in endocrine cells of the bronchial tract, the gastrointestinal tract, and the prostate. Among the 30 different tumour entities investigated, strong GPR19 expression was found in adenocarcinomas, typical and atypical carcinoids of the lung, and small cell lung cancer. To a lesser extent, the receptor was also present in large cell neuroendocrine carcinomas of the lung, medullary thyroid carcinomas, parathyroid adenomas, pheochromocytomas, and a subpopulation of pancreatic neuroendocrine neoplasms. In lung tumours, a negative correlation with the expression of the proliferation marker Ki-67 and a positive interrelationship with patient survival was observed. Overall, our results indicate that in adenocarcinomas and neuroendocrine tumours of the lung GPR19 may serve as a suitable diagnostic or therapeutic target.


Assuntos
Adenocarcinoma , Neoplasias das Glândulas Suprarrenais , Carcinoma Neuroendócrino , Neoplasias Pulmonares , Tumores Neuroendócrinos , Masculino , Animais , Coelhos , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/metabolismo , Receptores de Neurotransmissores/metabolismo
6.
J Cancer Res Clin Oncol ; 149(20): 18135-18160, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38006451

RESUMO

BACKGROUND: G protein-coupled receptors (GPCRs) have been shown to have an important role in tumor development and metastasis, and abnormal expression of GPCRs is significantly associated with poor prognosis of tumor patients. In this study, we analyzed the GPCRs-related gene (GPRGs) and tumor microenvironment (TME) in skin cutaneous melanoma (SKCM) to construct a prognostic model to help SKCM patients obtain accurate clinical treatment strategies. METHODS: SKCM expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential expression analysis, LASSO algorithm, and univariate and multivariate cox regression analysis were used to screen prognosis-related genes (GPR19, GPR146, S1PR2, PTH1R, ADGRE5, CXCR3, GPR143, and OR2I1P) and multiple prognosis-good immune cells; the data set was analyzed according to above results and build up a GPR-TME classifier. The model was further subjected to immune infiltration, functional enrichment, tumor mutational load, immunotherapy prediction, and scRNA-seq data analysis. Finally, cellular experiments were conducted to validate the functionality of the key gene GPR19 in the model. RESULTS: The findings indicate that high expression of GPRGs is associated with a poor prognosis in patients with SKCM, highlighting the significant role of GPRGs and the tumor microenvironment (TME) in SKCM development. Notably, the group characterized by low GPR expression and a high TME exhibited the most favorable prognosis and immunotherapeutic efficacy. Furthermore, cellular assays demonstrated that knockdown of GPR19 significantly reduced the proliferation, migration, and invasive capabilities of melanoma cells in A375 and A2058 cell lines. CONCLUSION: This study provides novel insights for the prognosis evaluation and treatment of melanoma, along with the identification of a new biomarker, GPR19.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Prognóstico , Neoplasias Cutâneas/genética , Microambiente Tumoral/genética , Biomarcadores , Receptores Acoplados a Proteínas G/genética , Proteínas do Tecido Nervoso , Receptores de Neurotransmissores
7.
Proc Natl Acad Sci U S A ; 120(42): e2306990120, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37831741

RESUMO

Hemispheric lateralization and its origins have been of great interest in neuroscience for over a century. The left-right asymmetry in cortical thickness may stem from differential maturation of the cerebral cortex in the two hemispheres. Here, we investigated the spatial pattern of hemispheric differences in cortical thinning during adolescence, and its relationship with the density of neurotransmitter receptors and homotopic functional connectivity. Using longitudinal data from IMAGEN study (N = 532), we found that many cortical regions in the frontal and temporal lobes thinned more in the right hemisphere than in the left. Conversely, several regions in the occipital and parietal lobes thinned less in the right (vs. left) hemisphere. We then revealed that regions thinning more in the right (vs. left) hemispheres had higher density of neurotransmitter receptors and transporters in the right (vs. left) side. Moreover, the hemispheric differences in cortical thinning were predicted by homotopic functional connectivity. Specifically, regions with stronger homotopic functional connectivity showed a more symmetrical rate of cortical thinning between the left and right hemispheres, compared with regions with weaker homotopic functional connectivity. Based on these findings, we suggest that the typical patterns of hemispheric differences in cortical thinning may reflect the intrinsic organization of the neurotransmitter systems and related patterns of homotopic functional connectivity.


Assuntos
Mapeamento Encefálico , Afinamento Cortical Cerebral , Adolescente , Humanos , Vias Neurais/fisiologia , Imageamento por Ressonância Magnética , Lateralidade Funcional/fisiologia , Receptores de Neurotransmissores , Encéfalo/fisiologia
8.
Biochim Biophys Acta Rev Cancer ; 1878(6): 189007, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37907132

RESUMO

This review summarizes emerging evidence that the neuroendocrine system is involved in the regulation of the tumor immune microenvironment (TIME) to influence cancer progression. The basis of the interaction between the neuroendocrine system and cancer is usually achieved by the infiltration of nerve fibers into the tumor tissue, which is called neurogenesis; the migration of cancer cells toward nerve fibers, which is called perineural invasion (PNI), and the neurotransmitters. In addition to the traditional role of neurotransmitters in neural communications, neurotransmitters are increasingly recognized as mediators of crosstalk between the nervous system, cancer cells, and the immune system. Recent studies have revealed that not only nerve fibers but also cancer cells and immune cells within the TIME can secrete neurotransmitters, exerting influence on both neurons and themselves. Furthermore, immune cells infiltrating the tumor environment have been found to express a wide array of neurotransmitter receptors. Hence, targeting these neurotransmitter receptors may promote the activity of immune cells in the tumor microenvironment and exert anti-tumor immunity. Herein, we discuss the crosstalk between the neuroendocrine system and tumor-infiltrating immune cells, which may provide feasible cancer immunotherapy options.


Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Sistemas Neurossecretores/patologia , Imunoterapia , Neurotransmissores/fisiologia , Receptores de Neurotransmissores , Microambiente Tumoral
9.
Cereb Cortex ; 33(23): 11320-11328, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37804242

RESUMO

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.


Assuntos
Encéfalo , Transcriptoma , Humanos , Masculino , Feminino , Encéfalo/patologia , Substância Cinzenta/patologia , Imageamento por Ressonância Magnética , Cognição , Mapeamento Encefálico/métodos , Neurotransmissores , Receptores de Neurotransmissores
10.
Nat Commun ; 14(1): 6009, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37752107

RESUMO

Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/patologia , Encéfalo/patologia , Neuroimagem , Córtex Cerebral/patologia , Dopamina , Receptores de Neurotransmissores
11.
Nat Commun ; 14(1): 6000, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37752115

RESUMO

Systematic spatial variation in micro-architecture is observed across the cortex. These micro-architectural gradients are reflected in neural activity, which can be captured by neurophysiological time-series. How spontaneous neurophysiological dynamics are organized across the cortex and how they arise from heterogeneous cortical micro-architecture remains unknown. Here we extensively profile regional neurophysiological dynamics across the human brain by estimating over 6800 time-series features from the resting state magnetoencephalography (MEG) signal. We then map regional time-series profiles to a comprehensive multi-modal, multi-scale atlas of cortical micro-architecture, including microstructure, metabolism, neurotransmitter receptors, cell types and laminar differentiation. We find that the dominant axis of neurophysiological dynamics reflects characteristics of power spectrum density and linear correlation structure of the signal, emphasizing the importance of conventional features of electromagnetic dynamics while identifying additional informative features that have traditionally received less attention. Moreover, spatial variation in neurophysiological dynamics is co-localized with multiple micro-architectural features, including gene expression gradients, intracortical myelin, neurotransmitter receptors and transporters, and oxygen and glucose metabolism. Collectively, this work opens new avenues for studying the anatomical basis of neural activity.


Assuntos
Mapeamento Encefálico , Encéfalo , Humanos , Encéfalo/fisiologia , Magnetoencefalografia , Neurofisiologia , Receptores de Neurotransmissores
12.
J Endod ; 49(12): 1641-1651.e6, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37769871

RESUMO

INTRODUCTION: Human dental pulp stem cells (hDPSCs) reside in specialized microenvironments in the dental pulp, termed "niches," which are composed of diverse cellular components including nerves. Sensory nerves can positively regulate the expansion and differentiation of pulp cells, while the biological effects of the sympathetic nervous system (SNS) on hDPSCs remain elusive. This study is devoted to investigating the effects and underlying mechanisms of the SNS on the proliferation and migration of hDPSCs. METHODS: The distribution of sympathetic nerve fibers in human dental pulp was examined by immunofluorescence staining of tyrosine hydroxylase. The concentration of norepinephrine in healthy and carious human dental pulp tissues was detected using enzyme-linked immunosorbent assay. RNA-sequencing was applied to identify the dominant sympathetic neurotransmitter receptor in hDPSCs. Seahorse metabolic assay, adenosine triphosphate assay, lactate assay, and mitochondrial DNA copy number were performed to determine the level of glycometabolism. Transwell assay, wound healing assay, 5-ethynyl-2'-deoxyuridine staining assay, cell cycle assay, and Cell Counting Kit-8 assay were conducted to analyze the migratory and proliferative capacities of hDPSCs. RESULTS: Sprouting of sympathetic nerve fibers and an increased concentration of norepinephrine were observed in inflammatory pulp tissues. Sympathetic nerve fibers were mainly distributed along blood vessels, and aldehyde dehydrogenase 1-positive hDPSCs resided in close proximity to neurovascular bundles. ADRA1B was identified as the major sympathetic neurotransmitter receptor expressed in hDPSCs, and its expression was enhanced in inflammatory pulp tissues. In addition, the SNS inhibited the proliferation and migration of hDPSCs through metabolic reprogramming via ADRA1B and its crosstalk with serine-threonine kinase and p38 mitogen-activated protein kinase signaling pathways. CONCLUSIONS: This study demonstrates that the SNS can shift the metabolism of hDPSCs from oxidative phosphorylation to anaerobic glycolysis via ADRA1B and its crosstalk with serine-threonine kinase and p38 mitogen-activated protein kinase signaling pathways, thereby inhibiting the proliferative and migratory abilities of hDPSCs. This metabolic shift may facilitate the maintenance of the quiescent state of hDPSCs.


Assuntos
Polpa Dentária , Proteínas Serina-Treonina Quinases , Humanos , Proliferação de Células , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/farmacologia , Diferenciação Celular/fisiologia , Células-Tronco/fisiologia , Sistema Nervoso Simpático , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologia , Norepinefrina/farmacologia , Norepinefrina/metabolismo , Receptores de Neurotransmissores/metabolismo , Receptores Adrenérgicos/metabolismo , Células Cultivadas
13.
Altern Ther Health Med ; 29(8): 356-365, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37632962

RESUMO

Context: Kidney renal clear-cell carcinoma (KIRC) is a malignant tumor. At an early stage, KIRC patients may experience only mild fever and fatigue or even no symptoms, and these early nonspecific indications can delay treatment. Neurotransmitters and their receptors may be very useful in determining tumorigenesis and predicting metastasis. Objective: The study intended to investigate the predictive value of neurotransmitter receptor-related genes (NRRGs) using public KIRC data, by determining the biological processes that implicate the prognostic NRRGs and establishing a predictive NR-related risk model, to provide an empirical basis for identifying and treating KIRC patients. Design: The research team performed a genetic case-control study. Setting: The study took place at Research Center of Health, Big Data Mining and Applications, Wannan Medical College, Wuhu, China. Methods: The research team: (1) obtained the transcriptome data related to KIRC from the Cancer Genome Atlas (TCGA) and ArrayExpress databases; (2) developed the differentially expressed NRRGs (DENRRGs) by identifying the NRRGs that intersected with DEGs in KIRC and normal samples; (3) carried out functional enrichment analyses of the DENRRGs; (4) screened the characteristic genes of the DENRRGs using machine learning; (5) created a predictive model using multivariate Cox analyses of the distinctive genes; (6) obtained independent prognostic factors for KIRC patients and established a nomograph model; (7) investigated the sensitivity of KIRC patients to therapeutic agents to examine the variations in immunological features between high-risk and low-risk individuals. Results: Differential analysis found that 115 NRRGs intersected with 5275 DEGs to provide 52 DENRRGs. Functional enrichment showed that DENRRGs were mainly involved in signal transduction in the nervous system. The machine learning on the 52 DENRRGs filtered out nine characteristic genes. Subsequently, the research team found eight prognostic biomarkers-histamine receptor H2 (HRH2), gamma-aminobutyric acid (GABA) receptor subunit epsilon (GABRE), cholinergic receptor nicotinic delta subunit (CHRND), glutamate receptor ionotropic subunit 2D (GRIN2D), glutamate metabotropic receptor 4 (GRM4), glycine receptor alpha 3 (GLRA3), cholinergic receptor nicotinic beta 4 subunit (CHRNB4), and cholinergic receptor muscarinic-1 (CHRM1)-and established a predictive model. Furthermore, the team precisely predicted the KIRC patients' prognoses using a nomogram that combined their ages, risk scores, and M stages. The infiltration levels of 21 immune cells also significantly differed between the high-risk and low-risk groups, with neutrophils having a significant positive correlation with GABRE and HRH2 and a significant negative correlation with CHRNB4 and GRM4. Finally, the 50% inhibitory concentration (IC50) values for various drugs, such as 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), Sunitinib, c-Jun N-terminal kinase (JNK) inhibitor VIII, and tanespimyci (X17.AAG) were significantly lower for high-risk group. Conclusions: By studying the relevance of biomarkers to the immunological microenvironment of KIRC, the current research team was able to propose a new predictive model for KIRC based on NRRGs, to offer a novel viewpoint for investigating KIRC. The study's results suggest new avenues for research into the pathophysiology and therapy of KIRC. Determining the precise molecular processes by which predictive biomarkers regulate KIRC requires further evidence and analysis.


Assuntos
Carcinoma , Receptores de Neurotransmissores , Humanos , Prognóstico , Estudos de Casos e Controles , Biomarcadores , Receptores Colinérgicos , Rim , Microambiente Tumoral , Receptor Muscarínico M1
14.
J Neurosci Res ; 101(11): 1728-1736, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37496289

RESUMO

Neuromedin U (NMU) belongs to a family of multifunctional neuropeptides that modulate the activity of several neural networks of the brain. Acting via metabotropic receptor NMUR2, NMU plays a role in the regulation of multiple systems, including energy homeostasis, stress responses, circadian rhythms, and endocrine signaling. The involvement of NMU signaling in the central regulation of important neurophysiological processes and its disturbances is a potential target for pharmacological modulation. Number of preclinical studies have proven that both modified NMU analogues such as PASR8-NMU or F4R8-NMU and designed NMUR2 agonists, for example, CPN-116, CPN-124 exhibit a distinct pharmacological activity especially when delivered transnasally. Their application can potentially be useful in the more convenient and safe treatment of obesity, eating disorders, Alzheimer's disease-related memory impairment, alcohol addiction, and sleep disturbances. Accumulating findings suggest that pharmacomodulation of the central NMU signaling may be a promising strategy in the treatment of several neuropsychiatric disorders.


Assuntos
Neuropeptídeos , Obesidade , Humanos , Neuropeptídeos/metabolismo , Homeostase , Encéfalo/metabolismo , Receptores de Neurotransmissores
15.
Cell Rep Methods ; 3(5): 100477, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37323572

RESUMO

Chemical neurotransmission occurs at specialized contacts where neurotransmitter release machinery apposes neurotransmitter receptors to underlie circuit function. A series of complex events underlies pre- and postsynaptic protein recruitment to neuronal connections. To better study synaptic development in individual neurons, we need cell-type-specific strategies to visualize endogenous synaptic proteins. Although presynaptic strategies exist, postsynaptic proteins remain less studied because of a paucity of cell-type-specific reagents. To study excitatory postsynapses with cell-type specificity, we engineered dlg1[4K], a conditionally labeled marker of Drosophila excitatory postsynaptic densities. With binary expression systems, dlg1[4K] labels central and peripheral postsynapses in larvae and adults. Using dlg1[4K], we find that distinct rules govern postsynaptic organization in adult neurons, multiple binary expression systems can concurrently label pre- and postsynapse in a cell-type-specific manner, and neuronal DLG1 can sometimes localize presynaptically. These results validate our strategy for conditional postsynaptic labeling and demonstrate principles of synaptic organization.


Assuntos
Drosophila , Sinapses , Animais , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Neurônios/fisiologia , Receptores de Neurotransmissores/metabolismo
16.
Nat Neurosci ; 26(7): 1281-1294, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37336976

RESUMO

Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas.


Assuntos
Mapeamento Encefálico , Córtex Cerebral , Receptores de Neurotransmissores , Idoso , Animais , Feminino , Humanos , Masculino , Ratos , Autorradiografia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Cognição , Espinhas Dendríticas , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Macaca fascicularis , Ratos Endogâmicos Lew , Receptor 5-HT1A de Serotonina/análise , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Colinérgicos/análise , Receptores Colinérgicos/metabolismo , Receptores Dopaminérgicos/análise , Receptores Dopaminérgicos/metabolismo , Receptores de Neurotransmissores/análise , Receptores de Neurotransmissores/metabolismo , Serotonina/metabolismo , Especificidade da Espécie , Bainha de Mielina/metabolismo
17.
Int J Mol Sci ; 24(10)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37239845

RESUMO

G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.


Assuntos
Proteômica , Transdução de Sinais , Humanos , Células HEK293 , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Envelhecimento/genética , Senescência Celular , Proteínas do Tecido Nervoso/metabolismo , Receptores de Neurotransmissores/metabolismo
18.
J Pharmacol Sci ; 152(3): 178-181, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37257945

RESUMO

Methylphenidate (MPH) and methamphetamine (METH) are the current treatments of choice for attention deficit/hyperactivity disorder. We previously reported that METH induces the release of dopamine (DA) and of the neurotransmitter candidate L-3,4-dihydroxyphenylalanine (L-DOPA). In contrast, we here found that MPH increased the DA release while it did not affect the L-DOPA release from the dorsolateral striatum. Nevertheless, MPH-induced hyperlocomotion was reduced in Gpr143 (L-DOPA receptor) gene-deficient (Gpr143-/y) mice. The rewarding effect and increased c-fos expression induced by MPH were also attenuated in Gpr143-/y mice. Together, these findings suggest that GPR143 is involved in the acute and chronic actions of MPH.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Metilfenidato , Camundongos , Animais , Metilfenidato/farmacologia , Levodopa/farmacologia , Receptores de Neurotransmissores , Dopamina/metabolismo , Metanfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia
19.
J Physiol ; 601(12): 2447-2472, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37026398

RESUMO

Gloeobacter violaceus ligand-gated ion channel (GLIC) is a prokaryotic orthologue of brain pentameric neurotransmitter receptors. Using whole-cell patch-clamp electrophysiology in a host cell line, we show that short-chain dicarboxylate compounds are positive modulators of pHo 5-evoked GLIC activity, with a rank order of action fumarate > succinate > malonate > glutarate. Potentiation by fumarate depends on intracellular pH, mainly as a result of a strong decrease of the pHo 5-evoked current when intracellular pH decreases. The modulating effect of fumarate also depends on extracellular pH, as fumarate is a weak inhibitor at pHo 6 and shows no agonist action at neutral pHo. A mutational analysis of residue dependency for succinate and fumarate effects, based on two carboxylate-binding pockets previously identified by crystallography (Fourati et al., 2020), shows that positive modulation involves both the inter-subunit pocket, homologous to the neurotransmitter-binding orthotopic site, and the intra-subunit (also called vestibular) pocket. An almost similar pattern of mutational impact is observed for the effect of caffeate, a known negative modulator. We propose, for both dicarboxylate compounds and caffeate, a model where the inter-subunit pocket is the actual binding site, and the region corresponding to the vestibular pocket is required either for inter-subunit binding itself, or for binding-to-gating coupling during the allosteric transitions involved in pore-gating modulation. KEY POINTS: Using a bacterial orthologue of brain pentameric neurotransmitter receptors, we show that the orthotopic/orthosteric agonist site and the adjacent vestibular region are functionally interdependent in mediating compound-elicited modulation. We propose that the two sites in the extracellular domain are involved 'in series', a mechanism which may have relevance for eukaryote receptors. We show that short-chain dicarboxylate compounds are positive modulators of the Gloeobacter violaceus ligand-gated ion channel (GLIC). The most potent compound identified is fumarate, known to occupy the orthotopic/orthosteric site in previously published crystal structures. We show that intracellular pH modulates GLIC allosteric transitions, as previously known for extracellular pH. We report a caesium to sodium permeability ratio (PCs /PNa ) of 0.54 for GLIC ion pore.


Assuntos
Cianobactérias , Canais Iônicos de Abertura Ativada por Ligante , Canais Iônicos de Abertura Ativada por Ligante/química , Cianobactérias/metabolismo , Receptores de Neurotransmissores/metabolismo , Succinatos/metabolismo , Proteínas de Bactérias/metabolismo
20.
Neuroimage ; 273: 120095, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37030412

RESUMO

Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their "RNA fingerprints", which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.


Assuntos
Hipocampo , Receptores de Neurotransmissores , Humanos , Hipocampo/fisiologia , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , RNA/metabolismo , Autorradiografia
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