RESUMO
BACKGROUND: Central Illustration : G Protein Subunit Beta 3 (GNB3) Variant Is Associated with Biochemical Changes in Brazilian Patients with Hypertension. BACKGROUND: Genes and their variants associated with environmental factors contribute to the development of the hypertensive phenotype. The G protein beta 3 subunit gene (GNB3) is involved in the intracellular signaling process, and its variants have been related to susceptibility to arterial hypertension. OBJECTIVE: To determine the association of the GNB3 variant (rs5443:C>T) with arterial hypertension, biochemical parameters, age, and obesity in hypertensive and normotensive individuals from Ouro Preto, Minas Gerais, Brazil. METHOD: The identification of variants was performed by real-time PCR, using the TaqMan® system, in 310 samples (155 hypertensive and 155 normotensive). Biochemical analyses (renal function, lipid profile and glycemia) were performed from the serum using UV/Vis spectrophotometry and ion-selective electrode. A multiple logistic regression model was used to identify factors associated with arterial hypertension. The analysis of continuous variables with normal distribution was performed using the unpaired Student's t test; non-normal data were analyzed using Mann-Whitney. P < 0.05 was considered significant. RESULTS: The rs5443:C>T variant was not associated with arterial hypertension in the evaluated population (p = 0.88). Regarding biochemical measures, the T allele was associated with high levels of triglycerides, glucose and uric acid in hypertensive individuals (p < 0.05). CONCLUSION: These results show the importance of genetic diagnosis to prevent the causes and consequences of diseases and imply that the GNB3 rs5443:C>T variant may be associated with changes in the biochemical profile in hypertensive individuals.
Assuntos
Proteínas Heterotriméricas de Ligação ao GTP , Hipertensão , Humanos , Alelos , Pressão Sanguínea/genética , Brasil , Genótipo , Hipertensão/genética , Subunidades Proteicas/genética , Proteínas Heterotriméricas de Ligação ao GTP/genéticaRESUMO
OBJECTIVES: The objective of this study was to present a broad view of how genetic polymorphisms in genes that control the rhythmicity and function of circadian rhythm may influence the etiology, pathophysiology and treatment of bipolar disorder (BD). METHODS: A bibliographic search was performed to identify and select papers reporting studies on variations in circadian genes and BD. A search of Medline, Google Scholar, Scopus, and Web of Science was carried out to review the literature. RESULTS: Several studies provide evidence of contributions of variations in circadian genes to disease etiology, pathophysiological variations and lithium drug response. Dysfunction of the sleep-wake cycle, an important brain function regulator, is indicated as the primary means by which circadian gene variations act in mood disorders. CONCLUSIONS: Investigations of the effects of circadian genes have suggested that the chronotype offers hope for guiding and improving management of patients with BD. However, BD is a disease of a complex nature and presents multiple endophenotypes determined by different associations between genetics and the environment. Thus, new genomic studies to delimit variations that may help improve the clinical condition of these patients are extremely important.
Assuntos
Transtorno Bipolar/genética , Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/genética , Fatores de Transcrição ARNTL/genética , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Proteínas CLOCK/genética , Proteínas de Ciclo Celular/genética , Transtornos Cronobiológicos/genética , Transtornos Cronobiológicos/psicologia , Endofenótipos , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Compostos de Lítio/uso terapêutico , Transtornos do Humor/complicações , Proteínas Circadianas Period/genética , Polimorfismo Genético , Transtornos do Sono do Ritmo Circadiano/psicologiaRESUMO
Collective cell migration is essential in many fundamental aspects of normal development, like morphogenesis, organ formation, wound healing, and immune responses, as well as in the etiology of severe pathologies, like cancer metastasis. In spite of the huge amount of data accumulated on cell migration, such a complex process involves many molecular actors, some of which still remain to be functionally characterized. One of these signals is the heterotrimeric G-protein pathway that has been studied mainly in gastrulation movements. Recently we have reported that Ric-8A, a GEF for Gα proteins, plays an important role in neural crest migration in Xenopus development. Xenopus neural crest cells, a highly migratory embryonic cell population induced at the border of the neural plate that migrates extensively in order to differentiate in other tissues during development, have become a good model to understand the dynamics that regulate cell migration. In this review, we aim to provide sufficient evidence supporting how useful Xenopus model with its different tools, such as explants and transplants, paired with improved in vivo imaging techniques, will allow us to tackle the multiple signaling mechanisms involved in neural crest cell migration.
Assuntos
Movimento Celular/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Morfogênese/genética , Xenopus laevis/genética , Animais , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Placa Neural/crescimento & desenvolvimento , Placa Neural/metabolismo , Transdução de Sinais/genética , Xenopus laevis/crescimento & desenvolvimentoRESUMO
Heterotrimeric G protein signaling plays major roles during different cellular events. However, there is a limited understanding of the molecular mechanisms underlying G protein control during embryogenesis. G proteins are highly conserved and can be grouped into four subfamilies according to sequence homology and function. To further studies on G protein function during embryogenesis, the present analysis identified four Gα subunits representative of the different subfamilies and determined their spatiotemporal expression patterns during Xenopus tropicalis embryogenesis. Each of the Gα subunit transcripts was maternally and zygotically expressed, and, as development progressed, dynamic expression patterns were observed. In the early developmental stages, the Gα subunits were expressed in the animal hemisphere and dorsal marginal zone. While expression was observed at the somite boundaries, in vascular structures, in the eye, and in the otic vesicle during the later stages, expression was mainly found in neural tissues, such as the neural tube and, especially, in the cephalic vesicles, neural crest region, and neural crest-derived structures. Together, these results support the pleiotropism and complexity of G protein subfamily functions in different cellular events. The present study constitutes the most comprehensive description to date of the spatiotemporal expression patterns of Gα subunits during vertebrate development.
Assuntos
Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Proteínas Heterotriméricas de Ligação ao GTP/biossíntese , Xenopus/genética , Sequência de Aminoácidos/genética , Animais , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hibridização In Situ , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Tubo Neural/crescimento & desenvolvimento , Tubo Neural/metabolismo , Transdução de Sinais , Somitos/crescimento & desenvolvimento , Somitos/metabolismo , Xenopus/crescimento & desenvolvimentoRESUMO
In fungi, heterotrimeric G proteins are key regulators of biological processes such as mating, virulence, morphology, among others. Mucor circinelloides is a model organism for many biological processes, and its genome contains the largest known repertoire of genes that encode putative heterotrimeric G protein subunits in the fungal kingdom: twelve Gα (McGpa1-12), three Gß (McGpb1-3), and three Gγ (McGpg1-3). Phylogenetic analysis of fungal Gα showed that they are divided into four distinct groups as reported previously. Fungal Gß and Gγ are also divided into four phylogenetic groups, and to our understanding this is the first report of a phylogenetic classification for fungal Gß and Gγ subunits. Almost all genes that encode putative heterotrimeric G subunits in M. circinelloides are differentially expressed during dimorphic growth, except for McGpg1 (Gγ) that showed very low mRNA levels at all developmental stages. Moreover, several of the subunits are expressed in a similar pattern and at the same level, suggesting that they constitute discrete complexes. For example, McGpb3 (Gß), and McGpg2 (Gγ), are co-expressed during mycelium growth, and McGpa1, McGpb2, and McGpg2, are co-expressed during yeast development. These findings provide the conceptual framework to study the biological role of these genes during M. circinelloides morphogenesis.
Assuntos
Proteínas Fúngicas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Mucor/crescimento & desenvolvimento , Mucor/metabolismo , Filogenia , Sequência de Aminoácidos , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Proteínas Heterotriméricas de Ligação ao GTP/química , Proteínas Heterotriméricas de Ligação ao GTP/genética , Dados de Sequência Molecular , Morfogênese , Mucor/química , Mucor/genética , Alinhamento de SequênciaRESUMO
Throughout evolution, organisms have created numerous mechanisms to sense and respond to their environment. One such highly conserved mechanism involves regulation by heterotrimeric G-protein complex comprised of alpha (Gα), beta (Gß) and gamma (Gγ) subunits. In plants, these proteins play important roles in signal transduction pathways related to growth and development including response to biotic and abiotic stresses and consequently affect yield. In this work, we have identified and characterized the complete heterotrimeric G-protein repertoire in the Capsicum annuum (Capsicum) genome which consists of one Gα, one Gß and three Gγ genes. We have also identified one RGS gene in the Capsicum genome that acts as a regulator of the G-protein signaling. Biochemical activities of the proteins were confirmed by assessing the GTP-binding and GTPase activity of the recombinant Gα protein and its regulation by the GTPase acceleration activity of the RGS protein. Interaction between different subunits was established using yeast- and plant-based analyses. Gene and protein expression profiles of specific G-protein components revealed interesting spatial and temporal regulation patterns, especially during root development and during fruit development and maturation. This research thus details the characterization of the first heterotrimeric G-protein family from a domesticated, commercially important vegetable crop.
Assuntos
Transdução de Sinais , Solanaceae/genética , Capsicum/genética , Capsicum/crescimento & desenvolvimento , Capsicum/metabolismo , Frutas/genética , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Proteínas Heterotriméricas de Ligação ao GTP/genética , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Especificidade de Órgãos , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Mapeamento de Interação de Proteínas , Proteínas RGS/genética , Proteínas RGS/metabolismoRESUMO
PURPOSE: The G-protein ß3-subunit gene C825T polymorphism (GNB3-C825T) has been reported to be associated with essential hypertension (EH), but results from previous studies are conflicting. The present study aimed at investigating the association between this polymorphism and risk of EH using a meta-analysis on the published studies. MATERIALS AND METHODS: PubMed, Embase, CBM (China Biological Medicine Database), Wanfang and VIP databases were searched to identify eligible studies published in English and Chinese before March 2013. Data were extracted using standardized methods. The association was assessed by the odds ratio (OR) with 95% confidence intervals (CI). Begg's test was used to measure publication bias. RESULTS: A total of 40 case-control studies containing 16,518 EH patients and 20,284 controls were involved in this meta-analysis. Overall, a significant association was found between GNB3 C825T polymorphism and risk of EH when all studies were pooled with a random-effects model for T versus C (OR=1.09, 95% CI: 1.04-1.19). In the subgroup analysis, the same association was found in overall Caucasian (T versus C, OR=1.16, 95% CI 1.08-1.24) and Chinese populations (TT versus CC, OR=1.23, 95% CI 1.06-1.57). No associations were detected between GNB3-C825T and the risk of EH overall in Asian and Japanese people. CONCLUSIONS: Meta-analysis results suggest that the GNB3-C825T polymorphism is associated with risk of EH in the overall population, the Caucasians and the Chinese. The effect of the variants on the expression levels and the possible functional role of the variants in EH should be addressed in further studies.
Assuntos
Predisposição Genética para Doença/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hipertensão/genética , Polimorfismo Genético/genética , China , Hipertensão Essencial , Frequência do Gene , Genótipo , Humanos , Fatores de RiscoRESUMO
TASK-2 (K2P5.1) is a background K(+) channel opened by extra- or intracellular alkalinisation that plays a role in renal bicarbonate handling, central chemoreception and cell volume regulation. Here, we present results that suggest that TASK-2 is also modulated by Gßγ subunits of heterotrimeric G protein. TASK-2 was strongly inhibited when GTP-γ-S was used as a replacement for intracellular GTP. No inhibition was present using GDP-ß-S instead. Purified Gßγ introduced intracellularly also inhibited TASK-2 independently of whether GTP or GDP-ß-S was present. The effects of GTP-γ-S and Gßγ subunits were abolished by neutralisation of TASK-2 C terminus double lysine residues K257-K258 or K296-K297. Use of membrane yeast two hybrid (MYTH) experiments and immunoprecipitation assays using tagged proteins gave evidence for a physical interaction between Gß1 and Gß2 subunits and TASK-2, in agreement with expression of these subunits in proximal tubule cells. Co-immunoprecipitation was impeded by mutating C terminus K257-K258 (but not K296-K297) to alanines. Gating by extra- or intracellular pH was unaltered in GTP-γ-S-insensitive TASK-2-K257A-K258A mutant. Shrinking TASK-2-expressing cells in hypertonic solution decreased the current to 36 % of its initial value. The same manoeuvre had a significantly diminished effect on TASK-2-K257A-K258A- or TASK-2-K296-K297-expressing cells, or in cells containing intracellular GDP-ß-S. Our data are compatible with the concept that TASK-2 channels are modulated by Gßγ subunits of heterotrimeric G protein. We propose that this modulation is a novel way in which TASK-2 can be tuned to its physiological functions.
Assuntos
Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Sequência de Aminoácidos , Animais , Subunidades beta da Proteína de Ligação ao GTP/genética , Subunidades gama da Proteína de Ligação ao GTP/genética , Guanosina Difosfato/análogos & derivados , Guanosina Difosfato/farmacologia , Células HEK293 , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Camundongos , Tionucleotídeos/farmacologia , Técnicas do Sistema de Duplo-HíbridoRESUMO
Purpose: The G-protein β3-subunit gene C825T polymorphism (GNB3-C825T) has been reported to be associated with essential hypertension (EH), but results from previous studies are conflicting. The present study aimed at investigating the association between this polymorphism and risk of EH using a meta-analysis on the published studies. Materials and Methods: PubMed, Embase, CBM (China Biological Medicine Database), Wanfang and VIP databases were searched to identify eligible studies published in English and Chinese before March 2013. Data were extracted using standardized methods. The association was assessed by the odds ratio (OR) with 95% confidence intervals (CI). Begg's test was used to measure publication bias. Results: A total of 40 case-control studies containing 16,518 EH patients and 20,284 controls were involved in this meta-analysis. Overall, a significant association was found between GNB3 C825T polymorphism and risk of EH when all studies were pooled with a random-effects model for T versus C (OR=1.09, 95% CI: 1.04-1.19). In the subgroup analysis, the same association was found in overall Caucasian (T versus C, OR=1.16, 95% CI 1.08-1.24) and Chinese populations (TT versus CC, OR=1.23, 95% CI 1.06-1.57). No associations were detected between GNB3-C825T and the risk of EH overall in Asian and Japanese people. Conclusions: Meta-analysis results suggest that the GNB3-C825T polymorphism is associated with risk of EH in the overall population, the Caucasians and the Chinese. The effect of the variants on the expression levels and the possible functional role of the variants in EH should be addressed in further studies.
Assuntos
Humanos , Predisposição Genética para Doença/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hipertensão/genética , Polimorfismo Genético/genética , China , Frequência do Gene , Genótipo , Fatores de RiscoRESUMO
Signaling via heterotrimeric G-proteins is evoked by agonist-mediated stimulation of seven transmembrane spanning receptors (GPCRs). During the last decade it has become apparent that Gα subunits can be activated by receptor-independent mechanisms. Ric-8 belongs to a highly conserved protein family that regulates heterotrimeric G-protein function, acting as a non-canonical guanine nucleotide exchange factors (GEF) over a subset of Gα subunits. In this review we discuss the roles of Ric-8 in the regulation of diverse cell functions, emphasizing the contribution of its multiple domain protein structure in these diverse functions.