Evgeny E Akkuratov

University of Oxford | OX · Weatherall Institute of Molecular Medicine

Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperex...

In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, w...

Electroencephalogram (EEG) interpretation plays a critical role in the clinical assessment of neurological conditions, most notably epilepsy. However, EEG recordings are typically analyzed manually by highly specialized and heavily trained personnel. Moreover, the low rate of capturing abnormal events during the procedure makes interpretation time-...

The sodium pump, Na,K‐ATPase, is an integral plasma membrane protein, expressed in all eukaryotic cells. Na,K‐ATPase transforms chemical energy from ATP into a gradient of Na+ and K+ over the plasma membrane by actively exporting three Na+ ions and importing two K+ ions for each hydrolyzed ATP. It is responsible for maintenance of the transmembrane...

The ion pump Na⁺,K⁺-ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na⁺,K⁺-ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy....

Cardiotonic steroids (CTS) are specific inhibitors and endogenous ligands of a key enzyme in the CNS—the Na+, K+-ATPase, which maintains and creates an ion gradient on the plasma membrane of neurons. CTS cause the activation of various signaling cascades and changes in gene expression in neurons and other cell types. It is known that intracerebrove...

The N-methyl-D-aspartate (NMDA) receptor plays an essential role in glutamatergic transmission and synaptic plasticity and researchers are seeking for different modulators of NMDA receptor function. One possible mechanism for its regulation could be through adjacent membrane proteins. NMDA receptors coprecipitate with Na,K-ATPase, indicating a pote...

Given its critical role in establishing ionic gradients in neurons and other excitable cells, functional disruption of the Na/K‐ATPase is expected to substantially compromise neurological homeostasis. However, to date only a few examples of spontaneous Na/K‐ATPase mutations have been identified in human patients. Here we describe a de novo Trp‐Arg...

Background: Chlamydia are ancient intracellular pathogens with reduced, though strikingly conserved genome. Despite their parasitic lifestyle and isolated intracellular environment, these bacteria managed to avoid accumulation of deleterious mutations leading to subsequent genome degradation characteristic for many parasitic bacteria. Results: W...

The ion pump Na⁺, K⁺–ATPase (NKA) is a receptor for the cardiotonic steroid ouabain. Subsaturating concentration of ouabain triggers intracellular calcium oscillations, stimulates cell proliferation and adhesion, and protects from apoptosis. However, it is controversial whether ouabain‐bound NKA is considered a signal transducer. To address this qu...

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging...

Chlamydia are ancient intracellular pathogens with reduced, though strikingly conserved genome. Despite their parasitic lifestyle and isolated intracellular environment, these bacteria managed to avoid accumulation of deleterious mutations leading to subsequent genome degradation characteristic for many parasitic bacteria. We report pan-genomic ana...

The N‐methyl‐d‐aspartate (NMDA) receptor plays an essential role for glutamatergic transmission and synaptic plasticity. Calcium influx via the NMDA receptor (NMDAR) activation modulates both long‐term potentiation (LTP) and long‐term depression (LTD). Hyperactivity of the NMDAR can trigger events leading to calcium mediated neurotoxicity, a common...

Synaptic proteins synucleins are found in pathologic aggregates in human brain during neurodegenerative diseases and in some tumors. Normal functions of these proteins in synapses are still unclear. In the present study, we used cDNA cloning to determine amino acid sequences of synucleins in the central nervous system of river lamprey (Lampetra flu...

The group of compounds of the cardiotonic steroid (CTS) class includes steroid compounds that inhibit Na⁺,K⁺-ATPase. Recently, a large amount of data has been accumulating on the important role of CTS in regulating brain function through binding to Na⁺,K⁺-ATPase, which can perform a receptor role and trigger intracellular signaling cascades. Intere...

Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan...

Binding to Na⁺,K⁺-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouaba...

Activation of extrasynaptic NMDA receptors by high glutamate concentrations is one of the key pathogenic factors following a stroke. For this reason, the search for efficient neuroprotective agents that could reduce glutamate toxicity is a pressing need. Ca²⁺ overload in response to glutamate leads to activation of signaling cascades in the cell an...

Cardiotonic steroid (CTS) ouabain is a well-established inhibitor of Na,K-ATPase capable of inducing signalling processes including changes in the activity of the mitogen activated protein kinases (MAPK) in various cell types. With increasing evidence of endogenous CTS in the blood and cerebrospinal fluid, it is of particular interest to study ouab...

The Na(+), K(+)-ATPase (NKA) differs from most other ion transporters not only in its capacity to maintain a steep electrochemical gradient across the plasma membrane but also as a receptor for a family of cardiotonic steroids, to which ouabain belongs. Studies from many groups, performed during the last fifteen years, have demonstrated that ouabai...

Ouabain stimulates activation of various signaling cascades such as protein kinase B (Akt) and Extracellular-signaling-regulated kinase 1/2 (ERK 1/2) in various cell lines. Retinoic acid (RA) is commonly used to induce neuroblastoma differentiation in cultures. Upon RA administration, human neuroblastoma cell line, SK-N-SH demonstrated neurite exte...

Mutations in ATP1A3, the gene encoding the neuron-specific sodium-potassium pump Na+, K+, ATPase alpha 3 subunit (NKAalpha3), lead to Rapid-onset Dystonia-Parkinsonism (RDP), a rare brain disorder arising during childhood. Symptoms, including dystonia and cognitive disorders, are triggered by intense stress. The most common mutation observed in RDP...

NMDA receptors play a crucial role in regulating synaptic plasticity and memory. Activation of NMDA receptors changes intracellular concentrations of Na(+) and K(+), which are subsequently restored by Na/K-ATPase. We used immunochemical and biochemical methods to elucidate the potential mechanisms of interaction between these two proteins. We obser...

Orthologous introns have identical positions relative to the coding sequence in orthologous genes of different species. By analyzing the complete genomes of five plants we generated a database of 40,512 orthologous intron groups of dicotyledonous plants, 28,519 orthologous intron groups of angiosperms, and 15,726 of land plants (moss and angiosperm...

Exposure of intact cells to selective inhibitors of Na(+)/K(+)-ATPase such as ouabain activates several growth-related cell signaling pathways. It has been suggested that the initial event of these pathways is the binding of ouabain to a preexisting complex of Src with Na(+)/K(+)-ATPase of the plasma membrane. The aim of this work was to evaluate t...

Most neurons co‐express two catalytic isoforms of Na,K‐ATPase, the ubiquitous α1, and the more selectively expressed α3. Although neurological syndromes are associated with α3 mutations, the specific role of this isoform is not completely understood. Here we used electrophysiology and sodium imaging to study the role of α3 in neurons expressing bot...

A primary culture of murine cerebellar neurons was used to induce oxidative stress resulting in the accumulation of reactive oxygen species (ROS) and activation of ERK 1/2 kinase. Short-term incubation (15 min) of cerebellar neurons with homocysteine (HC) or N-methyl-D-aspartate (NMDA) induced partial ERK 1/2 phosphorylation thus providing the acti...

Most neurons co-express two catalytic isoforms of Na,K-ATPase, the ubiquitous α1, and the more selectively expressed α3. Although neurological syndromes are associated with α3 mutations, the specific role of this isoform is not completely understood. Here, we used electrophysiological and Na⁺ imaging techniques to study the role of α3 in central ne...

The main properties of Na+ /K(+)-ATPase as a natural receptor for cardiotonic steroids have been discusses. Primary attention is focused on structural and functional differences between the alpha-subunit isoforms of Na+/K(+)-ATPase in different tissues. General information on the role of the Na pump in signaling cascades in kidney epithelial cells,...

Three-hour incubation of rat cerebellar granule cells with 0.1 μM ouabain increases intracellular levels of Ca2+ ions and reactive oxygen species (ROS) resulting in pronounced activation of Mitogen-Activated Protein Kinase (MAPK). Higher concentrations of ouabain induce further increases in MAPK activity. The activating effect of ouabain is attenua...

Activity of Na/K-ATPase isolated from bovine brain and kidney decreases during incubation with hydrogen peroxide proportionally to the incubation time and the concentration of the oxidant. Activity suppression is accompanied by a proportional decrease in the level of free SH-groups. Incubation of the oxidized enzyme with dithiothreitol restores the...