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1.
Philos Trans R Soc Lond B Biol Sci ; 379(1906): 20230240, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-38853555

RESUMO

Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. N-methyl-d-aspartic acid (NMDA) receptors, Ca2+ influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.


Assuntos
Giro do Cíngulo , Potenciação de Longa Duração , Receptores de AMPA , Receptores de N-Metil-D-Aspartato , Tupaiidae , Animais , Potenciação de Longa Duração/fisiologia , Giro do Cíngulo/fisiologia , Tupaiidae/fisiologia , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de AMPA/metabolismo , Adenilil Ciclases/metabolismo , Ácido Glutâmico/metabolismo , Masculino
2.
Nutrients ; 16(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892725

RESUMO

Xanthohumol (Xn) is an antioxidant flavonoid mainly extracted from hops (Humulus lupulus), one of the main ingredients of beer. As with other bioactive compounds, their therapeutic potential against different diseases has been tested, one of which is Alzheimer's disease (AD). Adenosine is a neuromodulatory nucleoside that acts through four different G protein-coupled receptors: A1 and A3, which inhibit the adenylyl cyclases (AC) pathway, and A2A and A2B, which stimulate this activity, causing either a decrease or an increase, respectively, in the release of excitatory neurotransmitters such as glutamate. This adenosinergic pathway, which is altered in AD, could be involved in the excitotoxicity process. Therefore, the aim of this work is to describe the effect of Xn on the adenosinergic pathway using cell lines. For this purpose, two different cellular models, rat glioma C6 and human neuroblastoma SH-SY5Y, were exposed to a non-cytotoxic 10 µM Xn concentration. Adenosine A1 and A2A, receptor levels, and activities related to the adenosine pathway, such as adenylate cyclase, protein kinase A, and 5'-nucleotidase, were analyzed. The adenosine A1 receptor was significantly increased after Xn exposure, while no changes in A2A receptor membrane levels or AC activity were reported. Regarding 5'-nucleotidases, modulation of their activity by Xn was noted since CD73, the extracellular membrane attached to 5'-nucleotidase, was significantly decreased in the C6 cell line. In conclusion, here we describe a novel pathway in which the bioactive flavonoid Xn could have potentially beneficial effects on AD as it increases membrane A1 receptors while modulating enzymes related to the adenosine pathway in cell cultures.


Assuntos
Adenosina , Flavonoides , Glioma , Humulus , Neuroblastoma , Propiofenonas , Receptor A1 de Adenosina , Humanos , Flavonoides/farmacologia , Ratos , Propiofenonas/farmacologia , Animais , Adenosina/metabolismo , Adenosina/farmacologia , Linhagem Celular Tumoral , Humulus/química , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , Glioma/metabolismo , Glioma/tratamento farmacológico , Receptor A1 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Receptor A2A de Adenosina/metabolismo
3.
Int J Mol Sci ; 25(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38891880

RESUMO

Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.


Assuntos
AMP Cíclico , Desoxiadenosinas , Simulação de Dinâmica Molecular , Neoplasias , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacologia , Desoxiadenosinas/química , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , AMP Cíclico/metabolismo , Trifosfato de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Simulação por Computador , Adenilil Ciclases/metabolismo
4.
Cell Mol Life Sci ; 81(1): 241, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38806811

RESUMO

Aspergillus ochraceus is the traditional ochratoxin A (OTA)-producing fungus with density-dependent behaviors, which is known as quorum sensing (QS) that is mediated by signaling molecules. Individual cells trend to adapt environmental changes in a "whole" flora through communications, allowing fungus to occupy an important ecological niche. Signals perception, transmission, and feedback are all rely on a signal network that constituted by membrane receptors and intracellular effectors. However, the interference of density information in signal transduction, which regulates most life activities of Aspergillus, have yet to be elucidated. Here we show that the G protein-coupled receptor (GPCR) to cAMP pathway is responsible for transmitting density information, and regulates the key point in life cycle of A. ochraceus. Firstly, the quorum sensing phenomenon of A. ochraceus is confirmed, and identified the density threshold is 103 spores/mL, which represents the low density that produces the most OTA in a series quorum density. Moreover, the GprC that classified as sugar sensor, and intracellular adenylate cyclase (AcyA)-cAMP-PKA pathway that in response to ligands glucose and HODEs are verified. Furthermore, GprC and AcyA regulate the primary metabolism as well as secondary metabolism, and further affects the growth of A. ochraceus during the entire life cycle. These studies highlight a crucial G protein signaling pathway for cell communication that is mediated by carbohydrate and oxylipins, and clarified a comprehensive effect of fungal development, which include the direct gene regulation and indirect substrate or energy supply. Our work revealed more signal molecules that mediated density information and connected effects on important adaptive behaviors of Aspergillus ochraceus, hoping to achieve comprehensive prevention and control of mycotoxin pollution from interrupting cell communication.


Assuntos
Aspergillus ochraceus , AMP Cíclico , Glucose , Percepção de Quorum , Transdução de Sinais , Aspergillus ochraceus/metabolismo , Aspergillus ochraceus/genética , Glucose/metabolismo , AMP Cíclico/metabolismo , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Ocratoxinas/metabolismo
5.
FEBS Open Bio ; 14(7): 1101-1115, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38710658

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is one of the major subtypes of heart failure (HF) and no effective treatments for this common disease exist to date. Cardiac fibrosis is central to the pathology of HF and a potential avenue for the treatment of HFpEF. To explore key fibrosis-related genes and pathways in the pathophysiological process of HFpEF, a mouse model of HFpEF was constructed. The relevant gene expression profiles were downloaded from the Gene Expression Omnibus database, and single-sample Gene Set Enrichment Analysis (ssGSEA) was performed targeting fibrosis-related pathways to explore differentially expressed genes (DEGs) in healthy control and HFpEF heart tissues with cross-tabulation analysis of fibrosis-related genes. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the identified fibrosis-related genes. The two most significant DEGs were selected, and further validation was conducted in HFpEF mice. The results indicated that myocardial fibrosis was significantly upregulated in HFpEF mice compared to healthy controls, while the ssGSEA results revealed significant differences in the enrichment of nine fibrosis-related pathways in HFpEF myocardial tissue, with 112 out of 798 DEGs being related to fibrosis. The in vivo results demonstrated that expression levels of resistin-like molecule gamma (Relmg) and adenylate cyclase 1 (Adcy1) in the heart tissues of HFpEF mice were significantly higher and lower, respectively, compared to healthy controls. Taken together, these results suggest that Relmg and Acdy1 as well as the fibrosis process may be potential targets for HFpEF treatment.


Assuntos
Adenilil Ciclases , Fibrose , Insuficiência Cardíaca , Animais , Camundongos , Fibrose/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Miocárdio/metabolismo , Miocárdio/patologia , Masculino , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL
6.
J Neurosci ; 44(26)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38777602

RESUMO

The striatum plays a central role in directing many complex behaviors ranging from motor control to action choice and reward learning. In our study, we used 55 male CFW mice with rapid decay linkage disequilibrium to systematically mine the striatum-related behavioral functional genes by analyzing their striatal transcriptomes and 79 measured behavioral phenotypic data. By constructing a gene coexpression network, we clustered the genes into 13 modules, with most of them being positively correlated with motor traits. Based on functional annotations as well as Fisher's exact and hypergeometric distribution tests, brown and magenta modules were identified as core modules. They were significantly enriched for striatal-related functional genes. Subsequent Mendelian randomization analysis verified the causal relationship between the core modules and dyskinesia. Through the intramodular gene connectivity analysis, Adcy5 and Kcnma1 were identified as brown and magenta module hub genes, respectively. Knock outs of both Adcy5 and Kcnma1 lead to motor dysfunction in mice, and KCNMA1 acts as a risk gene for schizophrenia and smoking addiction in humans. We also evaluated the cellular composition of each module and identified oligodendrocytes in the striatum to have a positive role in motor regulation.


Assuntos
Adenilil Ciclases , Corpo Estriado , Animais , Camundongos , Masculino , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Adenilil Ciclases/genética , Comportamento Animal/fisiologia , Redes Reguladoras de Genes/genética , Transcriptoma
7.
Mol Pain ; 20: 17448069241258110, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38744422

RESUMO

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.


Assuntos
Adenilil Ciclases , Colforsina , Giro do Cíngulo , Potenciação de Longa Duração , Animais , Camundongos , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Colforsina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Masculino , Receptores de AMPA/metabolismo , Camundongos Endogâmicos C57BL , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Cálcio/metabolismo
8.
Life Sci Alliance ; 7(7)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38719753

RESUMO

We recently reported that growth/differentiation factor 15 (GDF15) and its receptor GDNF family receptor alpha-like (GFRAL) are expressed in the periventricular germinal epithelium thereby regulating apical progenitor proliferation. However, the mechanisms are unknown. We now found GFRAL in primary cilia and altered cilia morphology upon GDF15 ablation. Mutant progenitors also displayed increased histone deacetylase 6 (Hdac6) and ciliary adenylate cyclase 3 (Adcy3) transcript levels. Consistently, microtubule acetylation, endogenous sonic hedgehog (SHH) activation and ciliary ADCY3 were all affected in this group. Application of exogenous GDF15 or pharmacological antagonists of either HDAC6 or ADCY3 similarly normalized ciliary morphology, proliferation and SHH signalling. Notably, Gdf15 ablation affected Hdac6 expression and cilia length only in the mutant periventricular niche, in concomitance with ciliary localization of GFRAL. In contrast, in the hippocampus, where GFRAL was not expressed in the cilium, progenitors displayed altered Adcy3 expression and SHH signalling, but Hdac6 expression, cilia morphology and ciliary ADCY3 levels remained unchanged. Thus, ciliary signalling underlies the effect of GDF15 on primary cilia elongation and proliferation in apical progenitors.


Assuntos
Adenilil Ciclases , Proliferação de Células , Cílios , Proteínas Hedgehog , Desacetilase 6 de Histona , Transdução de Sinais , Animais , Camundongos , Acetilação , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Proliferação de Células/genética , Cílios/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/genética , Camundongos Knockout , Células-Tronco/metabolismo , Células-Tronco/citologia
9.
J Headache Pain ; 25(1): 81, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760739

RESUMO

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.


Assuntos
Ansiedade , Peptídeo Relacionado com Gene de Calcitonina , Córtex Cerebral , Modelos Animais de Doenças , Transtornos de Enxaqueca , Ratos Sprague-Dawley , Animais , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Ratos , Masculino , Adenilil Ciclases/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
10.
Zoolog Sci ; 41(3): 302-313, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38809869

RESUMO

Sperm-specific cation channel (CatSper), sperm-specific Na + /H + exchanger (sNHE), and soluble adenylyl cyclase (sAC) are necessary in the signaling pathways to control sperm motility in many animals, whereas some animals have lost some or all of them. In the present study, we examined CatSper-uninvolved signaling for vigorous undulation of the undulating membrane that is attached to the sperm tail and gives thrust for forward motility in the internally fertilizing newt Cynops pyrrhogaster. Reverse-transcription PCR failed to detect sNHE in the newt sperm. However, the pH of sperm cytoplasm was raised under a high extracellular pH equivalent to that of egg jelly, where sperm motility is initiated by sperm motility-initiating substance (SMIS). Carbonic anhydrase XII/ XVI and SLC4A4/8 were suggested to be present in the sperm, and transported bicarbonates raised the intracellular pH. In egg jelly extract that contained SMIS, the anion transporter inhibitor DIDS weakened the undulation of the undulating membrane, while bicarbonates enhanced it. The cyclic AMP concentration was found to increase in sperm cytoplasm in the egg-jelly extract. An inhibitor of sAC (KH7) weakened the undulation of the undulating membrane, and dibutyryl cyclic AMP blocked the inhibitory effect. Inhibitor of transmembrane AC (DDA) limitedly affected the undulation. The undulation was weakened by an inhibitor of protein kinase A (H89), and by an inhibitor of transient receptor potential (TRP) channels (RN1747). Our results support the conclusions that the high pH of the egg jelly triggers a signaling pathway through sAC, PKA, and TRP channels, and coacts with SMIS to induce forward sperm motility.


Assuntos
Motilidade dos Espermatozoides , Espermatozoides , Masculino , Animais , Espermatozoides/fisiologia , Salamandridae/fisiologia , Fertilização/fisiologia , Concentração de Íons de Hidrogênio , Feminino , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Transdução de Sinais
11.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731872

RESUMO

Numerous studies suggest the involvement of adenosine-5'-triphosphate (ATP) and similar nucleotides in the pathophysiology of asthma. Androgens, such as testosterone (TES), are proposed to alleviate asthma symptoms in young men. ATP and uridine-5'-triphosphate (UTP) relax the airway smooth muscle (ASM) via purinergic P2Y2 and P2Y4 receptors and K+ channel opening. We previously demonstrated that TES increased the expression of voltage-dependent K+ (KV) channels in ASM. This study investigates how TES may potentiate ASM relaxation induced by ATP and UTP. Tracheal tissues treated with or without TES (control group) from young male guinea pigs were used. In organ baths, tracheas exposed to TES (40 nM for 48 h) showed enhanced ATP- and UTP-evoked relaxation. Tetraethylammonium, a K+ channel blocker, annulled this effect. Patch-clamp experiments in tracheal myocytes showed that TES also increased ATP- and UTP-induced K+ currents, and this effect was abolished with flutamide (an androgen receptor antagonist). KV channels were involved in this phenomenon, which was demonstrated by inhibition with 4-aminopyridine. RB2 (an antagonist of almost all P2Y receptors except for P2Y2), as well as N-ethylmaleimide and SQ 22,536 (inhibitors of G proteins and adenylyl cyclase, respectively), attenuated the enhancement of the K+ currents induced by TES. Immunofluorescence and immunohistochemistry studies revealed that TES did not modify the expression of P2Y4 receptors or COX-1 and COX-2, while we have demonstrated that this androgen augmented the expression of KV1.2 and KV1.5 channels in ASM. Thus, TES leads to the upregulation of P2Y4 signaling and KV channels in guinea pig ASM, enhancing ATP and UTP relaxation responses, which likely limits the severity of bronchospasm in young males.


Assuntos
Trifosfato de Adenosina , Adenilil Ciclases , Relaxamento Muscular , Músculo Liso , Testosterona , Traqueia , Uridina Trifosfato , Animais , Uridina Trifosfato/farmacologia , Uridina Trifosfato/metabolismo , Cobaias , Relaxamento Muscular/efeitos dos fármacos , Masculino , Trifosfato de Adenosina/metabolismo , Traqueia/metabolismo , Traqueia/efeitos dos fármacos , Testosterona/farmacologia , Testosterona/metabolismo , Adenilil Ciclases/metabolismo , Músculo Liso/metabolismo , Músculo Liso/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo
12.
Nat Metab ; 6(6): 1053-1075, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38684889

RESUMO

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.


Assuntos
Adenilil Ciclases , Tecido Adiposo Marrom , Temperatura Baixa , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Tecido Adiposo Marrom/metabolismo , Animais , Camundongos , Masculino , Humanos , Termogênese/genética , Metabolismo Energético , AMP Cíclico/metabolismo , Camundongos Knockout
13.
Nutrients ; 16(8)2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38674857

RESUMO

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between HTR1D and CDKAL1 and external eating; between HTR2A and emotional eating; between HTR2A, NPY2R, HTR1F, HTR3A, HTR2C, CXCR2, and T2D. Further analyses in a separate group revealed significant associations between metabolic syndrome (MetS) and the loci in CRP, ADCY3, GHRL, CDKAL1, BDNF, CHRM4, CHRM1, HTR3A, and AKT1 genes. MR results demonstrated an inverse causal relationship between external eating and glycated haemoglobin levels in the Volga-Ural sample. External eating influenced anthropometric traits such as body mass index, height, hip circumference, waist circumference, and weight in GWAS cohorts. Our findings suggest that eating patterns impact both anthropometric and metabolic traits.


Assuntos
Diabetes Mellitus Tipo 2 , Comportamento Alimentar , Grelina , Análise da Randomização Mendeliana , Fenótipo , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/etiologia , Feminino , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/etiologia , tRNA Metiltransferases/genética , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Pessoa de Meia-Idade , Índice de Massa Corporal , Adenilil Ciclases/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adulto , Circunferência da Cintura , Variação Genética
14.
Pflugers Arch ; 476(4): 457-465, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38581526

RESUMO

Soluble adenylyl cyclase (sAC) differs from transmembrane adenylyl cyclases (tmAC) in many aspects. In particular, the activity of sAC is not regulated by G-proteins but by the prevailing bicarbonate concentrations inside cells. Therefore, sAC serves as an exquisite intracellular pH sensor, with the capacity to translate pH changes into the regulation of localization and/or activity of cellular proteins involved in pH homeostasis. In this review, we provide an overview of literature describing the regulation of sAC activity by bicarbonate, pinpointing the importance of compartmentalization of intracellular cAMP signaling cascades. In addition, examples of processes involving proton and bicarbonate transport in different cell types, in which sAC plays an important regulatory role, were described in detail.


Assuntos
Adenilil Ciclases , AMP Cíclico , Adenilil Ciclases/metabolismo , AMP Cíclico/metabolismo , Bicarbonatos/metabolismo , Transdução de Sinais/fisiologia , Concentração de Íons de Hidrogênio
15.
Eur Biophys J ; 53(4): 239-247, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38625405

RESUMO

In this study, fluorescence recovery after photobleaching (FRAP) experiments were performed on RBC labeled by lipophilic fluorescent dye CM-DiI to evaluate the role of adenylyl cyclase cascade activation in changes of lateral diffusion of erythrocytes membrane lipids. Stimulation of adrenergic receptors with epinephrine (adrenaline) or metaproterenol led to the significant acceleration of the FRAP recovery, thus indicating an elevated membrane fluidity. The effect of the stimulation of protein kinase A with membrane-permeable analog of cAMP followed the same trend but was less significant. The observed effects are assumed to be driven by increased mobility of phospholipids resulting from the weakened interaction between the intermembrane proteins and RBC cytoskeleton due to activation of adenylyl cyclase signaling cascade.


Assuntos
Adenilil Ciclases , Membrana Eritrocítica , Recuperação de Fluorescência Após Fotodegradação , Fluidez de Membrana , Adenilil Ciclases/metabolismo , Fluidez de Membrana/efeitos dos fármacos , Humanos , Membrana Eritrocítica/metabolismo , Ativação Enzimática , Transdução de Sinais/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Epinefrina/farmacologia , Epinefrina/metabolismo
16.
Eur J Neurosci ; 59(11): 3134-3146, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38602078

RESUMO

Early life stress (ELS) exposure alters stress susceptibility in later life and affects vulnerability to stress-related disorders, but how ELS changes the long-lasting responsiveness of the stress system is not well understood. Zebrafish provides an opportunity to study conserved mechanisms underlying the development and function of the stress response that is regulated largely by the neuroendocrine hypothalamus-pituitary-adrenal/interrenal (HPA/I) axis, with glucocorticoids (GC) as the final effector. In this study, we established a method to chronically elevate endogenous GC levels during early life in larval zebrafish. To this end, we employed an optogenetic actuator, beggiatoa photoactivated adenylyl cyclase, specifically expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (pomc)-expression in the pituitary as well as upregulation of fkbp5 gene expression. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of the HPA/I axis by early-life GC exposure and its implications for vulnerability and resilience to stress in adulthood.


Assuntos
Glucocorticoides , Sistema Hipotálamo-Hipofisário , Larva , Optogenética , Peixe-Zebra , Animais , Optogenética/métodos , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Hidrocortisona/metabolismo , Estresse Psicológico/metabolismo , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Glândula Inter-Renal/metabolismo , Glândula Inter-Renal/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética
17.
Cell Commun Signal ; 22(1): 218, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38581012

RESUMO

Signal transduction through G protein-coupled receptors (GPCRs) has been a major focus in cell biology for decades. Numerous disorders are associated with GPCRs that utilize Gi proteins to inhibit adenylyl cyclase (AC) as well as regulate other effectors. Several early studies have successfully defined the AC-interacting domains of several members of Gαi by measuring the loss of activity upon homologous replacements of putative regions of constitutive active Gαi mutants. However, whether such findings can indeed be translated into the context of a receptor-activated Gαi have not been rigorously verified. To address this issue, an array of known and new chimeric mutations was introduced into GTPase-deficient Q204L (QL) and R178C (RC) mutants of Gαi1, followed by examinations on their ability to inhibit AC. Surprisingly, most chimeras failed to abolish the constitutive activity brought on by the QL mutation, while some were able to eliminate the inhibitory activity of RC mutants. Receptor-mediated inhibition of AC was similarly observed in the same chimeric constructs harbouring the pertussis toxin (PTX)-resistant C351I mutation. Moreover, RC-bearing loss-of-function chimeras appeared to be hyper-deactivated by endogenous RGS protein. Molecular docking revealed a potential interaction between AC and the α3/ß5 loop of Gαi1. Subsequent cAMP assays support a cooperative action of the α3/ß5 loop, the α4 helix, and the α4/ß6 loop in mediating AC inhibition by Gαi1-i3. Our results unveiled a notable functional divergence between constitutively active mutants and receptor-activated Gαi1 to inhibit AC, and identified a previously unknown AC-interacting domain of Gαi subunits. These results collectively provide valuable insights on the mechanism of AC inhibition in the cellular environment.


Assuntos
Adenilil Ciclases , GTP Fosfo-Hidrolases , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Simulação de Acoplamento Molecular , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Transporte , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
18.
Proc Natl Acad Sci U S A ; 121(16): e2322211121, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38593080

RESUMO

Adenosine 3',5'-cyclic monophosphate (cAMP) is a universal signaling molecule that acts as a second messenger in various organisms. It is well established that cAMP plays essential roles across the tree of life, although the function of cAMP in land plants has long been debated. We previously identified the enzyme with both adenylyl cyclase (AC) and cAMP phosphodiesterase (PDE) activity as the cAMP-synthesis/hydrolysis enzyme COMBINED AC with PDE (CAPE) in the liverwort Marchantia polymorpha. CAPE is conserved in streptophytes that reproduce with motile sperm; however, the precise function of CAPE is not yet known. In this study, we demonstrate that the loss of function of CAPE in M. polymorpha led to male infertility due to impaired sperm flagellar motility. We also found that two genes encoding the regulatory subunits of cAMP-dependent protein kinase (PKA-R) were also involved in sperm motility. Based on these findings, it is evident that CAPE and PKA-Rs act as a cAMP signaling module that regulates sperm motility in M. polymorpha. Therefore, our results have shed light on the function of cAMP signaling and sperm motility regulators in land plants. This study suggests that cAMP signaling plays a common role in plant and animal sperm motility.


Assuntos
Marchantia , Masculino , Animais , Marchantia/genética , AMP Cíclico/metabolismo , Motilidade dos Espermatozoides/genética , Sementes/metabolismo , Adenilil Ciclases/metabolismo , Espermatozoides/metabolismo
19.
Calcif Tissue Int ; 114(4): 430-443, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38483547

RESUMO

Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride channel 7 (CLCN7). Adenylate cyclase, which catalyzes the formation of cAMP, is critical for lysosomal acidification in osteoclasts. We found reduced cAMP levels in ADO2 osteoclasts compared to wild-type (WT) osteoclasts, leading us to examine whether regulating cAMP would improve ADO2 osteoclast activity. Although forskolin, a known activator of adenylate cyclase and cAMP levels, negatively affected osteoclast number, it led to an overall increase in ADO2 and WT osteoclast resorption activity in vitro. Next, we examined cAMP hydrolysis by the phosphodiesterase 4 (PDE4) proteins in ADO2 versus WT osteoclasts. QPCR analysis revealed higher expression of the three major PDE4 subtypes (4a, 4b, 4d) in ADO2 osteoclasts compared in WT, consistent with reduced cAMP levels in ADO2 osteoclasts. In addition, we found that the PDE4 antagonists, rolipram and roflumilast, stimulated ADO2 and WT osteoclast formation in a dose-dependent manner. Importantly, roflumilast and rolipram displayed a concentration-dependent increase in osteoclast resorption activity which was greater in ADO2 than WT osteoclasts. Moreover, treatment with roflumilast rescued cAMP levels in ADO2 OCLs. The key findings from our studies demonstrate that osteoclasts from ADO2 mice exhibit reduced cAMP levels and PDE4 inhibition rescues cAMP levels and ADO2 osteoclast activity dysfunction in vitro. The mechanism of action of PDE4 inhibitors and their ability to reduce the high bone mass of ADO2 mice in vivo are currently under investigation. Importantly, these studies advance the understanding of the mechanisms underlying the ADO2 osteoclast dysfunction which is critical for the development of therapeutic approaches to treat clinically affected ADO2 patients.


Assuntos
Aminopiridinas , Benzamidas , Reabsorção Óssea , Inibidores da Fosfodiesterase 4 , Humanos , Camundongos , Animais , Rolipram/farmacologia , Rolipram/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/metabolismo , Osteoclastos/metabolismo , Adenilil Ciclases/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Canais de Cloreto/genética , Ciclopropanos
20.
Cell Rep Methods ; 4(4): 100740, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38521059

RESUMO

Intracellular signaling plays essential roles in various cell types. In the central nervous system, signaling cascades are strictly regulated in a spatiotemporally specific manner to govern brain function; for example, presynaptic cyclic adenosine monophosphate (cAMP) can enhance the probability of neurotransmitter release. In the last decade, channelrhodopsin-2 has been engineered for subcellular targeting using localization tags, but optogenetic tools for intracellular signaling are not well developed. Therefore, we engineered a selective presynaptic fusion tag for photoactivated adenylyl cyclase (bPAC-Syn1a) and found its high localization at presynaptic terminals. Furthermore, an all-optical electrophysiological method revealed rapid and robust short-term potentiation by bPAC-Syn1a at brain stem-amygdala synapses in acute brain slices. Additionally, bPAC-Syn1a modulated mouse immobility behavior. These results indicate that bPAC-Syn1a can manipulate presynaptic cAMP signaling in vitro and in vivo. The all-optical manipulation technique developed in this study can help further elucidate the dynamic regulation of various cellular functions.


Assuntos
Adenilil Ciclases , AMP Cíclico , Plasticidade Neuronal , Terminações Pré-Sinápticas , Animais , Masculino , Camundongos , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , AMP Cíclico/metabolismo , Células HEK293 , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Optogenética/métodos , Terminações Pré-Sinápticas/metabolismo , Ratos
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