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1.
BMC Med Genet ; 21(1): 64, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228492

RESUMO

BACKGROUND: The calcium-selective channel TRPV6 (transient receptor potential cation channel subfamily V member 6) is crucial for maternal-fetal calcium transport across the placenta. TRPV6 mutations have recently been associated with an antenatally severe under-mineralising skeletal dysplasia accompanied by postnatal biochemical abnormalities. This is the first post-mortem report in a patient with TRPV6 skeletal dysplasia. CASE PRESENTATION: The female infant had severe antenatal and postnatal skeletal abnormalities by 20 weeks gestation and was ventilator-dependent from birth. These skeletal abnormalities were apparent at an earlier gestational age than in previous reported cases and a more severe clinical course ensued. Biochemical and skeletal abnormalities, including bone density, improved postnatally but cardiac arrest at 4 months of age led to withdrawal of intensive care. Compound heterozygous TRPV6 variants (c.1978G > C p.(Gly660Arg) and c.1528C > T p.(Arg510Ter)) were identified on exome sequencing. Post-mortem identified skeletal abnormalities but no specific abnormalities in other organ systems. No placental pathology was found, multi-organ histological features reflected prolonged intensive care only. Post-mortem macroscopic examination indicated reduced thoracic size and short, pale and pliable ribs. Histological examination identified reduced number of trabeculae in the diaphyses (away from the growth plates), whereas metaphyses showed adequate mineralisation and normal number of trabeculae, but with slightly enlarged reactive chondrocytes, indicating post-natal skeletal growth recovery. Post-mortem radiological findings demonstrated improved bone density, improved rib width, healed fractures, although ribs were still shorter than normal. Long bones (especially humerus and femur) had improved from initial poorly defined metaphyses and reduced bone density to sharply defined metaphyses, prominent growth restart lines in distal diaphyses and bone-in-bone appearance along diaphyses. CONCLUSIONS: This case provide bone histological confirmation that human skeletal development is compromised in the presence of TRPV6 pathogenic variants. Post-mortem findings were consistent with abnormal in utero skeletal mineralisation due to severe calcium deficit from compromised placental calcium transfer, followed by subsequent phenotypic improvement with adequate postnatal calcium availability. Significant skeletal recovery occurs in the early weeks of postnatal life in TRPV6 skeletal dysplasia.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos/patologia , Canais de Cálcio/genética , Desenvolvimento Infantil/fisiologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Canais de Cátion TRPV/genética , Autopsia , Desenvolvimento Ósseo/genética , Osso e Ossos/anormalidades , Calcificação Fisiológica/genética , Cálcio/metabolismo , Canais de Cálcio/análise , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Osteocondrodisplasias/reabilitação , Parto/fisiologia , Canais de Cátion TRPV/análise
2.
BMC Med Genet ; 21(1): 44, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111194

RESUMO

BACKGROUND: Abnormal calcium homeostasis related to the development of hypertension. As the key regulator of intracellular calcium concentration, voltage-dependent calcium channels (VDCCs), the variations in these genes may have important effects on the development of hypertension. Here we evaluate VDCCs variability with respect to hypertension in the Dai ethnic group of China. METHODS: A total of 1034 samples from Dai individuals were collected, of which 495 were used as cases, and 539 were used as controls. Blood pressure was measured using a standard mercury measurement method, three times with a rest for 5 min, and the average was used for analyses. Seventeen single nucleotide polymorphisms (SNPs) in the four protein-coding genes (CACNA1A, CACNA1C, CACNA1S, CACNB2) of VDCCs were identified by multiplex PCR-SNP typing technique. Chi-square tests and regression models were used to analyse the associations of SNPs with hypertension. RESULTS: The results of chi-square tests showed that the allele frequencies of 5 SNPs were significantly different between the case and the control groups (P < 0.05), but the statistical significance was lost after Bonferroni's correction. However, after adjusting for BMI, age, sex and other factors by logistic regression analyses, the results showed that 5 SNPs consistent with chi-square tests (rs2365293, rs17539088, rs16917217, rs61839222 and rs10425859) were still statistically positive. CONCLUSIONS: This finding suggested that the significant association of these SNPs with hypertension may be noteworthy in future studies.


Assuntos
Grupo com Ancestrais do Continente Asiático , Canais de Cálcio/genética , Hipertensão/etnologia , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , Estudos de Casos e Controles , China/epidemiologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
3.
Adv Exp Med Biol ; 1131: 445-469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646520

RESUMO

Store-operated Ca2+ entry (SOCE) is a ubiquitous mechanism for Ca2+ influx in mammalian cells with important physiological implications. Since the discovery of SOCE more than three decades ago, the mechanism that communicates the information about the amount of Ca2+ accumulated in the intracellular Ca2+ stores to the plasma membrane channels and the nature of these channels have been matters of intense investigation and debate. The stromal interaction molecule-1 (STIM1) has been identified as the Ca2+ sensor of the intracellular Ca2+ compartments that activates the store-operated channels. STIM1 regulates two types of store-dependent channels: the Ca2+ release-activated Ca2+ (CRAC) channels, formed by Orai1 subunits, that conduct the highly Ca2+ selective current I CRAC and the cation permeable store-operated Ca2+ (SOC) channels, which consist of Orai1 and TRPC1 proteins and conduct the non-selective current I SOC. While the crystal structure of Drosophila CRAC channel has already been solved, the architecture of the SOC channels still remains unclear. The dynamic interaction of STIM1 with the store-operated channels is modulated by a number of proteins that either support the formation of the functional STIM1-channel complex or protect the cell against Ca2+ overload.


Assuntos
Canais de Cálcio , Cálcio , Transporte de Íons , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Transporte de Íons/genética , Molécula 1 de Interação Estromal/metabolismo
4.
Adv Exp Med Biol ; 1131: 625-648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646528

RESUMO

Free Calcium (Ca2+) is an important and universal signalling entity in all cells, red blood cells included. Although mature mammalian red blood cells are believed to not contain organelles as Ca2+ stores such as the endoplasmic reticulum or mitochondria, a 20,000-fold gradient based on a intracellular Ca2+ concentration of approximately 60 nM vs. an extracellular concentration of 1.2 mM makes Ca2+-permeable channels a major signalling tool of red blood cells. However, the internal Ca2+ concentration is tightly controlled, regulated and maintained primarily by the Ca2+ pumps PMCA1 and PMCA4. Within the last two decades it became evident that an increased intracellular Ca2+ is associated with red blood cell clearance in the spleen and promotes red blood cell aggregability and clot formation. In contrast to this rather uncontrolled deadly Ca2+ signals only recently it became evident, that a temporal increase in intracellular Ca2+ can also have positive effects such as the modulation of the red blood cells O2 binding properties or even be vital for brief transient cellular volume adaptation when passing constrictions like small capillaries or slits in the spleen. Here we give an overview of Ca2+ channels and Ca2+-regulated channels in red blood cells, namely the Gárdos channel, the non-selective voltage dependent cation channel, Piezo1, the NMDA receptor, VDAC, TRPC channels, CaV2.1, a Ca2+-inhibited channel novel to red blood cells and i.a. relate these channels to the molecular unknown sickle cell disease conductance Psickle. Particular attention is given to correlation of functional measurements with molecular entities as well as the physiological and pathophysiological function of these channels. This view is in constant progress and in particular the understanding of the interaction of several ion channels in a physiological context just started. This includes on the one hand channelopathies, where a mutation of the ion channel is the direct cause of the disease, like Hereditary Xerocytosis and the Gárdos Channelopathy. On the other hand it applies to red blood cell related diseases where an altered channel activity is a secondary effect like in sickle cell disease or thalassemia. Also these secondary effects should receive medical and pharmacologic attention because they can be crucial when it comes to the life-threatening symptoms of the disease.


Assuntos
Canais de Cálcio , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Eritrócitos/fisiologia , Doenças Hematológicas/fisiopatologia , Humanos , Mutação
5.
Ecotoxicol Environ Saf ; 188: 109909, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31740235

RESUMO

Mn3O4 nanoparticles (NPs) are used increasingly in various fields due to their excellent physiochemical properties. Previous studies have documented that Mn-based nanomaterials resulted in excess reactive oxygen species (ROS) generation and dopamine (DA) reduction both in vivo and in vitro experiments. However, little is known about the mechanism of ROS production and DA decrease induced by Mn-based nanomaterials. The present study was carried out to elucidate the mechanism of the co-incubation model of dopaminergic neuron PC12 cells and the synthesized Mn3O4 NPs. The results demonstrated that exposure to Mn3O4 NPs reduced cell viability, increased level of lactate dehydrogenase (LDH), triggered oxidative stress and induced apoptosis. Notably, the level of ROS was remarkably increased (>10-fold) with Mn3O4 NPs exposure. We also found that mitochondrial calcium Ca2+ uniporter (MCU) was up-regulated and the mitochondrial Ca2+ concentration ([Ca2+]mito) increased induced by Mn3O4 NPs in PC12 cells. Furthermore, the MCU inhibitor RuR significantly attenuated Mn3O4 NPs-induced [Ca2+]mito, ROS production and apoptosis. In PC12 cells, the decrease of DA content was mainly due to the downregulation of DOPA decarboxylase (DDC) expression caused by Mn3O4 NPs treatment. The expression of proteins related to DA storage system was not significantly affected by treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Óxidos/toxicidade , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sobrevivência Celular , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Compostos de Manganês/química , Nanopartículas Metálicas/química , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
6.
Molecules ; 24(24)2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861069

RESUMO

Peripheral nerve injury (PNI) leads to a series of cellular and molecular events necessary for axon regeneration and reinnervation of target tissues, among which inflammation is crucial for the orchestration of all these processes. Macrophage activation underlies the pathogenesis of PNI and is characterized by morphological/phenotype transformation from proinflammatory (M1) to an anti-inflammatory (M2) type with different functions in the inflammatory and reparative process. The aim of this study was to evaluate influence of the vitamin B (B1, B2, B3, B5, B6, and B12) complex on the process of neuroinflammation that is in part regulated by l-type CaV1.2 calcium channels. A controlled transection of the motor branch of the femoral peripheral nerve was used as an experimental model. Animals were sacrificed after 1, 3, 7, and 14 injections of vitamin B complex. Isolated nerves were used for immunofluorescence analysis. Treatment with vitamin B complex decreased expression of proinflammatory and increased expression of anti-inflammatory cytokines, thus contributing to the resolution of neuroinflammation. In parallel, B vitamins decreased the number of M1 macrophages that expressed the CaV1.2 channel, and increased the number of M2 macrophages that expressed this channel, suggesting their role in M1/M2 transition after PNI. In conclusion, B vitamins had the potential for treatment of neuroinflammation and neuroregeneration and thereby might be an effective therapy for PNI in humans.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Complexo Vitamínico B/farmacologia , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Citocinas/metabolismo , Imunofluorescência , Regulação da Expressão Gênica , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/metabolismo
7.
Nat Commun ; 10(1): 4509, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586055

RESUMO

Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation.


Assuntos
Sinalização do Cálcio/fisiologia , Diferenciação Celular/genética , Epigênese Genética/fisiologia , Infarto do Miocárdio/patologia , Miofibroblastos/fisiologia , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Fibrose , Glicólise/fisiologia , Humanos , Ácidos Cetoglutáricos/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Miocárdio/citologia , Miocárdio/patologia , Cultura Primária de Células
8.
BMC Neurol ; 19(1): 246, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640633

RESUMO

BACKGROUND: To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine. CASE PRESENTATION: A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside. If however she remained awake the attacks would continue unabated. A presumed diagnosis of episodic ataxia type 2 was made and she became attack free on acetazolamide without recurrence. Genetic testing demonstrated a novel pathogenic variant in CACNA1A on chromosome 19. This pathogenic variant has not been previously reported in the literature and is suggested to truncate the CACNA1A polypeptide by introducing a premature stop codon. CONCLUSION: A case of episodic ataxia type 2 with a novel pathogenic variant in CACNA1A is described. Interestingly, the patient's symptoms would completely alleviate with sleep which suggests a sleep modulated channelopathy. The mechanisms by which sleep could potentially alter this pathogenic variant are hypothesized. A potential link to sleep alleviated migraine is suggested. Further study of this novel pathogenic variant may help us understand not only how sleep can modulate episodic ataxia type 2, but also migraine.


Assuntos
Ataxia/genética , Canais de Cálcio/genética , Sono , Acetazolamida/uso terapêutico , Adulto , Ataxia/complicações , Ataxia/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Canalopatias/genética , Códon sem Sentido , Feminino , Humanos , Transtornos de Enxaqueca/genética , Linhagem
9.
Theor Appl Genet ; 132(12): 3425-3437, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31562568

RESUMO

KEY MESSAGE: A major QTL conferring tolerance to radish (Raphanus sativus) root cracking was mapped for the first time and two calcium regulatory genes were identified that positively associated with the cracking phenomenon. Root cracking is a severe physiological disorder that significantly decreases the yield and commercial value of radish. The genetic and physiological mechanisms underlying this root cracking disorder have not been characterized. In this study, quantitative trait loci (QTLs) putatively associated with radish root cracking were mapped. Ten QTLs were distributed in six linkage groups, among these QTLs, 'RCr1' in LG1 was detected over 3 consecutive years and was considered to be a major QTL for root cracking. The QTL 'RCr1' was responsible for 4.47-18.11% of variance in the root cracking phenotype. We subsequently identified two candidate genes, RsANNAT and RsCDPK. Both genes encode proteins involved in calcium binding, ion transport, and Ca2+ signal transduction, which are important for regulating plant development and adaptations to the environment. These genes were co-localized to the major QTL region. Additionally, we analyzed physiological changes (i.e., root firmness, cell wall content, and cell-wall-bound calcium content) in two parental lines during different developmental stages. Moreover, we observed that the RsANNAT and RsCDPK expression levels are positively correlated with Ca2+ contents in the roots of the cracking-tolerant '835' cultivar. Thus, these genes may influence root cracking. The data provided herein may support the useful information to understand root cracking behavior in radish and may enable breeders to develop new cultivars exhibiting increased tolerance to root and fruit cracking.


Assuntos
Raízes de Plantas/crescimento & desenvolvimento , Locos de Características Quantitativas , Raphanus/genética , Canais de Cálcio/genética , Sinalização do Cálcio , Mapeamento Cromossômico , Genes de Plantas , Ligação Genética , Raízes de Plantas/genética , Polimorfismo de Nucleotídeo Único
10.
Ren Fail ; 41(1): 842-849, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31488014

RESUMO

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and enlargement and dysfunction of the kidneys. The Consortium of Radiologic Imaging Studies of the Polycystic Kidney Disease (CRISP) cohort revealed that 89.1% had either a PKD1 or PKD2 mutation. Of the CRISP patients with a genetic cause detected, mutations in PKD1 accounted for 85%, while mutations in the PKD2 accounted for the remaining 15%. Here, we report exome sequencing of 16 Saudi patients diagnosed with ADPKD and 16 ethnically matched controls. Methods: Exome sequencing was performed using combinatorial probe-anchor synthesis and improved DNA Nanoballs technology on BGISEQ-500 sequencers (BGI, China) using the BGI Exome V4 (59 Mb) Kit. Identified variants were validated with Sanger sequencing. Results: With the exception of GC-rich exon 1, we obtained excellent coverage of PKD1 (mean read depth = 88) including both duplicated and non-duplicated regions. Of nine patients with typical ADPKD presentations (bilateral symmetrical kidney involvement, positive family history, concordant imaging, and kidney function), four had protein truncating PKD1 mutations, one had a PKD1 missense mutation, and one had a PKD2 mutation. These variants have not been previously observed in the Saudi population. In seven clinically diagnosed ADPKD cases but with atypical features, no PKD1 or PKD2 mutations were identified, but rare predicted pathogenic heterozygous variants were found in cystogenic candidate genes including PKHD1, PKD1L3, EGF, CFTR, and TSC2. Conclusions: Mutations in PKD1 and PKD2 are the most common cause of ADPKD in Saudi patients with typical ADPKD. Abbreviations: ADPKD: Autosomal dominant polycystic kidney disease; CFTR: Cystic fibrosis transmembrane conductance regulator; EGF: Epidermal growth factor; MCIC: Mayo Clinic Imaging Classification; PKD: Polycystic kidney disease; TSC2: Tuberous sclerosis complex 2.


Assuntos
Rim Policístico Autossômico Dominante/genética , Adulto , Idoso , Árabes/genética , Canais de Cálcio/genética , Estudos de Casos e Controles , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Análise Mutacional de DNA , Fator de Crescimento Epidérmico/genética , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Receptores de Superfície Celular/genética , Arábia Saudita , Canais de Cátion TRPP/genética , Tomografia Computadorizada por Raios X , Proteína 2 do Complexo Esclerose Tuberosa/genética , Sequenciamento Completo do Exoma
11.
PLoS One ; 14(7): e0218738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260485

RESUMO

C. elegans neuronal system constitutes the ideal framework for studying simple, yet realistic, neuronal activity, since the whole nervous system is fully characterized with respect to the exact number of neurons and the neuronal connections. Most recent efforts are devoted to investigate and clarify the signal processing and functional connectivity, which are at the basis of sensing mechanisms, signal transmission, and motor control. In this framework, a refined modelof whole neuron dynamics constitutes a key ingredient to describe the electrophysiological processes, both at thecellular and at the network scale. In this work, we present Hodgkin-Huxley-based models of ion channels dynamics black, built on data available both from C. elegans and from other organisms, expressing homologous channels. We combine these channel models to simulate the electrical activity oftwo among the most studied neurons in C. elegans, which display prototypical dynamics of neuronal activation, the chemosensory AWCON and the motor neuron RMD. Our model properly describes the regenerative responses of the two cells. We analyze in detail the role of ion currents, both in wild type and in in silico knockout neurons. Moreover, we specifically investigate the behavior of RMD, identifying a heterogeneous dynamical response which includes bistable regimes and sustained oscillations. We are able to assess the critical role of T-type calcium currents, carried by CCA-1 channels, and leakage currents in the regulation of RMD response. Overall, our results provide new insights in the activity of key C. elegans neurons. The developed mathematical framework constitute a basis for single-cell and neuronal networks analyses, opening new scenarios in the in silico modeling of C. elegans neuronal system.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Modelos Neurológicos , Neurônios Motores/fisiologia , Rede Nervosa/fisiologia , Células Receptoras Sensoriais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Caenorhabditis elegans/citologia , Proteínas de Caenorhabditis elegans/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Simulação por Computador , Expressão Gênica , Transporte de Íons , Neurônios Motores/citologia , Rede Nervosa/citologia , Canais de Potássio/genética , Canais de Potássio/metabolismo , Células Receptoras Sensoriais/citologia , Análise de Célula Única/métodos , Canais de Sódio/genética , Canais de Sódio/metabolismo
12.
PLoS One ; 14(7): e0219266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291293

RESUMO

INTRODUCTION: Over the past few decades, the prevalence of hypertension has dramatically increased in Sub-Saharan Africa. Poor adherence has been identified as a major cause of failure to control hypertension. Scarce data are available in Africa. AIMS: We assessed adherence to medication and identified socioeconomics, clinical and treatment factors associated with low adherence among hypertensive patients in 12 sub-Saharan African countries. METHOD: We conducted a cross-sectional survey in urban clinics of both low and middle income countries. Data were collected by physicians on demographics, treatment and clinical data among hypertensive patients attending the clinics. Adherence was assessed by questionnaires completed by the patients. Factors associated with low adherence were investigated using logistic regression with a random effect on countries. RESULTS: There were 2198 individuals from 12 countries enrolled in the study. Overall, 678 (30.8%), 738 (33.6%), 782 (35.6%) participants had respectively low, medium and high adherence to antihypertensive medication. Multivariate analysis showed that the use of traditional medicine (OR: 2.28, 95%CI [1.79-2.90]) and individual wealth index (low vs. high wealth: OR: 1.86, 95%CI [1.35-2.56] and middle vs. high wealth: OR: 1.42, 95%CI [1.11-1.81]) were significantly and independently associated with poor adherence to medication. In stratified analysis, these differences in adherence to medication according to individual wealth index were observed in low-income countries (p<0.001) but not in middle-income countries (p = 0.17). In addition, 26.5% of the patients admitted having stopped their treatment due to financial reasons and this proportion was 4 fold higher in the lowest than highest wealth group (47.8% vs 11.4%) (p<0.001). CONCLUSION: This study revealed the high frequency of poor adherence in African patients and the associated factors. These findings should be useful for tailoring future programs to tackle hypertension in low income countries that are better adapted to patients, with a potential associated enhancement of their effectiveness.


Assuntos
Anti-Hipertensivos/efeitos adversos , Hipertensão/tratamento farmacológico , Adesão à Medicação , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Canais de Cálcio/genética , Estudos Transversais , Países em Desenvolvimento/economia , Feminino , Humanos , Hipertensão/economia , Hipertensão/epidemiologia , Renda , Masculino , Pessoa de Meia-Idade , Pobreza/economia , Prevalência , Fatores Socioeconômicos , Inquéritos e Questionários
13.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331039

RESUMO

Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.


Assuntos
Canais de Cálcio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Animais , Biomarcadores , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Ensaios Clínicos como Assunto , Regulação da Expressão Gênica , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Transtornos Mentais/diagnóstico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Terapia de Alvo Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade , Resultado do Tratamento
14.
Nature ; 572(7768): 260-264, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341286

RESUMO

In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on 'fitness fingerprints', which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell's membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8-17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19-21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.


Assuntos
Canais de Cálcio/metabolismo , Proliferação de Células , Proteínas de Drosophila/metabolismo , Neoplasias/patologia , Isoformas de Proteínas/metabolismo , Animais , Canais de Cálcio/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Drosophila melanogaster , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Isoformas de Proteínas/genética
15.
PLoS Pathog ; 15(6): e1007746, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194856

RESUMO

Toxoplasma gondii is a prevalent protozoan parasite that can infect any nucleated cell but cannot replicate outside of its host cell. Toxoplasma is auxotrophic for several nutrients including arginine, tryptophan, and purines, which it must acquire from its host cell. The demands of parasite replication rapidly deplete the host cell of these essential nutrients, yet Toxoplasma successfully manages to proliferate until it lyses the host cell. In eukaryotic cells, nutrient starvation can induce the integrated stress response (ISR) through phosphorylation of an essential translation factor eIF2. Phosphorylation of eIF2 lowers global protein synthesis coincident with preferential translation of gene transcripts involved in stress adaptation, such as that encoding the transcription factor ATF4 (CREB2), which activates genes that modulate amino acid metabolism and uptake. Here, we discovered that the ISR is induced in host cells infected with Toxoplasma. Our results show that as Toxoplasma depletes host cell arginine, the host cell phosphorylates eIF2 via protein kinase GCN2 (EIF2AK4), leading to induced ATF4. Increased ATF4 then enhances expression of the cationic amino acid transporter CAT1 (SLC7A1), resulting in increased uptake of arginine in Toxoplasma-infected cells. Deletion of host GCN2, or its downstream effectors ATF4 and CAT1, lowers arginine levels in the host, impairing proliferation of the parasite. Our findings establish that Toxoplasma usurps the host cell ISR to help secure nutrients that it needs for parasite replication.


Assuntos
Arginina/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Biossíntese de Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Arginina/genética , Transporte Biológico Ativo/genética , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Toxoplasmose/genética , Toxoplasmose/patologia
16.
Nat Plants ; 5(6): 581-588, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31182842

RESUMO

Chloroplasts are integral to sensing biotic and abiotic stress in plants, but their role in transducing Ca2+-mediated stress signals remains poorly understood1,2. Here we identify cMCU, a member of the mitochondrial calcium uniporter (MCU) family, as an ion channel mediating Ca2+ flux into chloroplasts in vivo. Using a toolkit of aequorin reporters targeted to chloroplast stroma and the cytosol in cMCU wild-type and knockout lines, we provide evidence that stress-stimulus-specific Ca2+ dynamics in the chloroplast stroma correlate with expression of the channel. Fast downstream signalling events triggered by osmotic stress, involving activation of the mitogen-activated protein kinases (MAPK) MAPK3 and MAPK6, and the transcription factors MYB60 and ethylene-response factor 6 (ERF6), are influenced by cMCU activity. Relative to wild-type plants, cMCU knockouts display increased resistance to long-term water deficit and improved recovery on rewatering. Modulation of stromal Ca2+ in specific processing of stress signals identifies cMCU as a component of plant environmental sensing.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Canais de Cálcio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Cloroplastos/metabolismo , Cloroplastos/metabolismo , Proteínas Mitocondriais/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Cálcio/metabolismo , Canais de Cálcio/genética , Proteínas de Transporte de Cátions/genética , Proteínas de Cloroplastos/genética , Cloroplastos/genética , Escherichia coli , Técnicas de Inativação de Genes , Sistema de Sinalização das MAP Quinases , Proteínas Mitocondriais/genética , Pressão Osmótica
17.
Nat Commun ; 10(1): 2659, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201323

RESUMO

In contrast to the plasma membrane, the vacuole membrane has not yet been associated with electrical excitation of plants. Here, we show that mesophyll vacuoles from Arabidopsis sense and control the membrane potential essentially via the K+-permeable TPC1 and TPK channels. Electrical stimuli elicit transient depolarization of the vacuole membrane that can last for seconds. Electrical excitability is suppressed by increased vacuolar Ca2+ levels. In comparison to wild type, vacuoles from the fou2 mutant, harboring TPC1 channels insensitive to luminal Ca2+, can be excited fully by even weak electrical stimuli. The TPC1-loss-of-function mutant tpc1-2 does not respond to electrical stimulation at all, and the loss of TPK1/TPK3-mediated K+ transport affects the duration of TPC1-dependent membrane depolarization. In combination with mathematical modeling, these results show that the vacuolar K+-conducting TPC1 and TPK1/TPK3 channels act in concert to provide for Ca2+- and voltage-induced electrical excitability to the central organelle of plant cells.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Canais de Cálcio/metabolismo , Potenciais da Membrana/fisiologia , Vacúolos/fisiologia , Proteínas de Arabidopsis/genética , Canais de Cálcio/genética , Sinalização do Cálcio/fisiologia , Membranas Intracelulares/fisiologia , Mutação com Perda de Função , Células do Mesofilo/citologia , Células do Mesofilo/fisiologia , Plantas Geneticamente Modificadas , Potássio/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo
18.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172971

RESUMO

Dexamethasone inhibits mucin secretion considering the primary option for treating acute asthma exacerbation. However, the mechanism underlying dexamethasone-induced decreased in mucosecretion is unclear. Recent studies have reported that dexamethasone exerts an inhibitory effect on mucosecretion in the lung by modulating the expression of calcium processing genes. However, the expression of the calcium processing genes in the trachea is not examined yet. Thus, the present study is the first to report the localization of calcium processing proteins such as transient receptor potential vanilloid-4 (Trpv4), transient receptor potential vanilloid-6 (Trpv6), calbindin-D9k (CaBP-9k) and plasma membrane Ca2+-ATPase 1 (Pmca1) in the mouse trachea and their glucocorticoid-induced response. In this study, mice were subcutaneously injected with dexamethasone for 5 days, and their tracheal samples were collected by dividing the trachea into the cervical, and thoracic sections based on its anatomical structure. The localization of TRPV4, TRPV6, CaBP-9k, and PMCA1 proteins was detected in the tracheal epithelium, submucosal glands, cartilages and muscles. Dexamethasone treatment downregulated the mRNA expression of the four calcium processing genes and mucin producing genes. The dexamethasone-induced decrease in the secretion of mucosubstances in the trachea was determined by performing Alcian blue-periodic acid-Schiff staining. Thus, the findings of the present study suggest that glucocorticoids simultaneously can regulate the expression of calcium processing genes and tracheal mucosecretion.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Mucosa Respiratória/metabolismo , Proteína G de Ligação ao Cálcio S100/genética , Proteína G de Ligação ao Cálcio S100/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
19.
Cell ; 177(5): 1252-1261.e13, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31080062

RESUMO

Mitochondrial calcium uptake is crucial to the regulation of eukaryotic Ca2+ homeostasis and is mediated by the mitochondrial calcium uniporter (MCU). While MCU alone can transport Ca2+ in primitive eukaryotes, metazoans require an essential single membrane-spanning auxiliary component called EMRE to form functional channels; however, the molecular mechanism of EMRE regulation remains elusive. Here, we present the cryo-EM structure of the human MCU-EMRE complex, which defines the interactions between MCU and EMRE as well as pinpoints the juxtamembrane loop of MCU and extended linker of EMRE as the crucial elements in the EMRE-dependent gating mechanism among metazoan MCUs. The structure also features the dimerization of two MCU-EMRE complexes along an interface at the N-terminal domain (NTD) of human MCU that is a hotspot for post-translational modifications. Thus, the human MCU-EMRE complex, which constitutes the minimal channel components among metazoans, provides a framework for future mechanistic studies on MCU.


Assuntos
Canais de Cálcio/metabolismo , Ativação do Canal Iônico/fisiologia , Complexos Multiproteicos/metabolismo , Multimerização Proteica/fisiologia , Canais de Cálcio/genética , Células HEK293 , Humanos , Complexos Multiproteicos/genética , Domínios Proteicos , Estrutura Secundária de Proteína
20.
Neuron ; 103(1): 66-79.e12, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31104951

RESUMO

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.


Assuntos
Canais de Cálcio/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Canais de Cálcio/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Células HEK293 , Humanos , Luz , Neurotransmissores/metabolismo , Optogenética , Gravidez , Isoformas de Proteínas/genética , Ratos , Vesículas Sinápticas/fisiologia
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