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1.
Na/K-ATPase: Their role in cell adhesion and migration in cancer.
Silva, CID, Gonçalves-de-Albuquerque, CF, Moraes, BPT, Garcia, DG, Burth, P
Biochimie. 2021;:1-8
Abstract
Na/K-ATPase (NKA) is a p-type transmembrane enzyme formed by three different subunits (α, β, and γ gamma). Primarily responsible for transporting sodium and potassium through the cell membrane, it also plays a critical role in intracellular signaling. The activation of diverse intracellular pathways may trigger cell death, survival, or even cell proliferation. Changes in the NKA functions or expression in isoforms subunits impact pathological conditions, such as cancer. The NKA function affects cell adhesion, motility, and migration, which are different in the physiological and pathological states. All enzyme subunits take part in the cell adhesion process, with the β subunit being the most studied. Thus, herein we aim to highlight NKA' central role in cell adhesion, motility, and migration in cancer cells.
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Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)-Report of two cases and literature review.
Biela, M, Rydzanicz, M, Szymanska, K, Pieniawska-Smiech, K, Lewandowicz-Uszynska, A, Chruszcz, J, Benben, L, Kuzior-Plawiak, M, Szyld, P, Jakubiak, A, et al
Molecular genetics & genomic medicine. 2021;(9):e1772
Abstract
BACKGROUND Variants in ATP1A3 cause well-known phenotypes-alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype-phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756-two acronyms are proposed for the moment-FIPWE (fever-induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia). MATERIALS AND METHODS Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty-three cases from literature were analyzed to define and strengthen the genotype-phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu). CONCLUSIONS Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements.
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GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism.
Monticone, S, Buffolo, F, Tetti, M, Veglio, F, Pasini, B, Mulatero, P
European journal of endocrinology. 2018;(3):R101-R111
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Abstract
Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.
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Na+ , K+ -ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells.
Bolotta, A, Visconti, P, Fedrizzi, G, Ghezzo, A, Marini, M, Manunta, P, Messaggio, E, Posar, A, Vignini, A, Abruzzo, PM
Autism research : official journal of the International Society for Autism Research. 2018;(10):1388-1403
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Abstract
Na+ , K+ -ATPase (NKA) activity, which establishes the sodium and potassium gradient across the cell membrane and is instrumental in the propagation of the nerve impulses, is altered in a number of neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD). In the present work, we examined a wide range of biochemical and cellular parameters in the attempt to understand the reason(s) for the severe decrease in NKA activity in erythrocytes of ASD children that we reported previously. NKA activity in leukocytes was found to be decreased independently from alteration in plasma membrane fluidity. The different subunits were evaluated for gene expression in leukocytes and for protein expression in erythrocytes: small differences in gene expression between ASD and typically developing children were not apparently paralleled by differences in protein expression. Moreover, no gross difference in erythrocyte plasma membrane oxidative modifications was detectable, although oxidative stress in blood samples from ASD children was confirmed by increased expression of NRF2 mRNA. Interestingly, gene expression of some NKA subunits correlated with clinical features. Excess inhibitory metals or ouabain-like activities, which might account for NKA activity decrease, were ruled out. Plasma membrane cholesterol, but not phosphatidylcholine and phosphatidlserine, was slighty decreased in erythrocytes from ASD children. Although no compelling results were obtained, our data suggest that alteration in the erytrocyte lipid moiety or subtle oxidative modifications in NKA structure are likely candidates for the observed decrease in NKA activity. These findings are discussed in the light of the relevance of NKA in ASD. Autism Res 2018, 11: 1388-1403. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY The activity of the cell membrane enzyme NKA, which is instrumental in the propagation of the nerve impulses, is severely decreased in erythrocytes from ASD children and in other brain disorders, yet no explanation has been provided for this observation. We strived to find a biological/biochemical cause of such alteration, but most queries went unsolved because of the complexity of NKA regulation. As NKA activity is altered in many brain disorders, we stress the relevance of studies aimed at understanding its regulation in ASD.
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The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview.
Amarelle, L, Lecuona, E
International journal of molecular sciences. 2018;(8)
Abstract
Since being first described more than 60 years ago, Na,K-ATPase has been extensively studied, while novel concepts about its structure, physiology, and biological roles continue to be elucidated. Cardiac glycosides not only inhibit the pump function of Na,K-ATPase but also activate intracellular signal transduction pathways, which are important in many biological processes. Recently, antiviral effects have been described as a novel feature of Na,K-ATPase inhibition with the use of cardiac glycosides. Cardiac glycosides have been reported to be effective against both DNA viruses such as cytomegalovirus and herpes simplex and RNA viruses such as influenza, chikungunya, coronavirus, and respiratory syncytial virus, among others. Consequently, cardiac glycosides have emerged as potential broad-spectrum antiviral drugs, with the great advantage of targeting cell host proteins, which help to minimize resistance to antiviral treatments, making them a very promising strategy against human viral infections. Here, we review the effect of cardiac glycosides on viral biology and the mechanisms by which these drugs impair the replication of this array of different viruses.
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Intense interval training in healthy older adults increases skeletal muscle [3H]ouabain-binding site content and elevates Na+,K+-ATPase α2 isoform abundance in Type II fibers.
Wyckelsma, VL, Levinger, I, Murphy, RM, Petersen, AC, Perry, BD, Hedges, CP, Anderson, MJ, McKenna, MJ
Physiological reports. 2017;(7)
Abstract
Young adults typically adapt to intense exercise training with an increased skeletal muscle Na+,K+-ATPase (NKA) content, concomitant with reduced extracellular potassium concentration [K+] during exercise and enhanced exercise performance. Whether these changes with longitudinal training occur in older adults is unknown and was investigated here. Fifteen older adults (69.4 ± 3.5 years, mean ± SD) were randomized to either 12 weeks of intense interval training (4 × 4 min at 90-95% peak heart rate), 3 days/week (IIT, n = 8); or no exercise controls (n = 7). Before and after training, participants completed an incremental cycle ergometer exercise test until a rating of perceived exertion of 17 (very hard) on a 20-point scale was attained, with measures of antecubital venous [K+]v Participants underwent a resting muscle biopsy prior to and at 48-72 h following the final training session. After IIT, the peak exercise work rate (25%), oxygen uptake (16%) and heart rate (6%) were increased (P < 0.05). After IIT, the peak exercise plasma [K+]v tended to rise (P = 0.07), while the rise in plasma [K+]v relative to work performed (nmol.L-1J-1) was unchanged. Muscle NKA content increased by 11% after IIT (P < 0.05). Single fiber measurements, increased in NKA α2 isoform in Type II fibers after IIT (30%, P < 0.05), with no changes to the other isoforms in single fibers or homogenate. Thus, intense exercise training in older adults induced an upregulation of muscle NKA, with a fiber-specific increase in NKA α2 abundance in Type II fibers, coincident with increased muscle NKA content and enhanced exercise performance.
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Changes in erythrocyte ATPase activity under different pathological conditions.
Kherd, AA, Helmi, N, Balamash, KS, Kumosani, TA, Al-Ghamdi, SA, Qari, M, Huwait, EA, Yaghmoor, SS, Nabil, A, Al-Ghamdi, MA, et al
African health sciences. 2017;(4):1204-1210
Abstract
BACKGROUND Studies have shown that Na+-K+ ATPase activity was altered in disrupted red blood cell membranes and this enzyme is believed to be the site of active transport of Na+ and K+ in intact red blood cells. The enzyme is often referred to as Na+-K+ pump because it pumps Na+ out and K+ into the cell against gradients with the concomitant hydrolysis of intracellular ATP. OBJECTIVE The aim of this study was to find out the possibility of using Na+-K+-ATPase activity as a biomarker for the diagnosis of individuals with different physiological conditions. MATERIALS AND METHODS The activity of Na+-K+ ATPase was determined in blood samples collected from different pathological and physiological conditions such as pregnancy, smoking, diabetes and renal dysfunction compared with healthy subjects matched for age and sex. RESULTS The Na+-K+ ATPase activity in pregnancy (0.094 ± 0.0051 µM Pi/min. mg protein), smoking (0.064 ± 0.0011 µM), diabetes (0.047 µM 0.002 µM) and kidney disease (0.069 ± 0.0014 µM) was higher compared to the measurements in healthy individuals (0.0081 ± 0.0031 µM). CONCLUSION Na+-K+ATPase specific activity is a biomarker for the diagnosis of individuals with different physiological diseases.
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The Na, K-ATPase β-Subunit Isoforms Expression in Glioblastoma Multiforme: Moonlighting Roles.
Rotoli, D, Cejas, MM, Maeso, MD, Pérez-Rodríguez, ND, Morales, M, Ávila, J, Mobasheri, A, Martín-Vasallo, P
International journal of molecular sciences. 2017;(11)
Abstract
Glioblastoma multiforme (GBM) is the most common form of malignant glioma. Recent studies point out that gliomas exploit ion channels and transporters, including Na, K-ATPase, to sustain their singular growth and invasion as they invade the brain parenchyma. Moreover, the different isoforms of the β-subunit of Na, K-ATPase have been implicated in regulating cellular dynamics, particularly during cancer progression. The aim of this study was to determine the Na, K-ATPase β subunit isoform subcellular expression patterns in all cell types responsible for microenvironment heterogeneity of GBM using immunohistochemical analysis. All three isoforms, β1, β2/AMOG (Adhesion Molecule On Glia) and β3, were found to be expressed in GBM samples. Generally, β1 isoform was not expressed by astrocytes, in both primary and secondary GBM, although other cell types (endothelial cells, pericytes, telocytes, macrophages) did express this isoform. β2/AMOG and β3 positive expression was observed in the cytoplasm, membrane and nuclear envelope of astrocytes and GFAP (Glial Fibrillary Acidic Protein) negative cells. Interestingly, differences in isoforms expression have been observed between primary and secondary GBM: in secondary GBM, β2 isoform expression in astrocytes was lower than that observed in primary GBM, while the expression of the β3 subunit was more intense. These changes in β subunit isoforms expression in GBM could be related to a different ionic handling, to a different relationship between astrocyte and neuron (β2/AMOG) and to changes in the moonlighting roles of Na, K-ATPase β subunits as adaptor proteins and transcription factors.
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The role of red blood cell deformability and Na,K-ATPase function in selected risk factors of cardiovascular diseases in humans: focus on hypertension, diabetes mellitus and hypercholesterolemia.
Radosinska, J, Vrbjar, N
Physiological research. 2016;:S43-54
Abstract
Deformability of red blood cells (RBC) is the ability of RBC to change their shape in order to pass through narrow capillaries in circulation. Deterioration in deformability of RBC contributes to alterations in microcirculatory blood flow and delivery of oxygen to tissues. Several factors are responsible for maintenance of RBC deformability. One of them is the Na,K-ATPase known as crucial enzyme in maintenance of intracellular ionic homeostasis affecting thus regulation of cellular volume and consequently RBC deformability. Decreased deformability of RBC has been found to be the marker of adverse outcomes in cardiovascular diseases (CVD) and the presence of cardiovascular risk factors influences rheological properties of the blood. This review summarizes knowledge concerning the RBC deformability in connection with selected risk factors of CVD, including hypertension, hyperlipidemia, and diabetes mellitus, based exclusively on papers from human studies. We attempted to provide an update on important issues regarding the role of Na,K-ATPase in RBC deformability. In patients suffering from hypertension as well as diabetes mellitus the Na,K-ATPase appears to be responsible for the changes leading to alterations in RBC deformability. The triggering factor for changes of RBC deformability during hypercholesterolemia seems to be the increased content of cholesterol in erythrocyte membranes.
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The Expression of Water and Ion Channels in Diffuse Alveolar Damage Is Not Dependent on DAD Etiology.
Pires-Neto, RC, Del Carlo Bernardi, F, Alves de Araujo, P, Mauad, T, Dolhnikoff, M
PloS one. 2016;(11):e0166184
Abstract
INTRODUCTION Aquaporins and ion channels are membrane proteins that facilitate the rapid movement of water and solutes across biological membranes. Experimental and in vitro studies reported that the function of these channels and pulmonary edema resolution are impaired in acute lung injury (ALI). Although current evidence indicates that alveolar fluid clearance is impaired in patients with ALI/diffuse alveolar damage (DAD), few human studies have addressed the alterations in pulmonary channels in this clinical condition. Additionally, it is not known whether the primary cause of DAD is a relevant variable for the channel dysfunction. METHODS Autopsied lungs of 43 patients with acute respiratory failure (ARF) due to DAD of three different etiologies, non-pulmonary sepsis, H1N1 viral infection and leptospirosis, were compared to 18 normal lungs. We quantified the expression of aquaporin (AQP) 1, AQP3, AQP5, epithelial Na+ channel (ENaC) and sodium potassium ATPase (Na-K-ATPase) in the alveolar septum using immunohistochemistry and image analysis. RESULTS The DAD group presented with increased expression of AQP3, AQP5 and Na-K-ATPase and decreased expression of ENaC compared to controls. However, there was no difference in protein expression within the DAD groups of different etiologies. CONCLUSION Water and ion channels are altered in patients with ARF due to DAD. The cause of DAD does not seem to influence the level of impairment of these channels.