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Fedorenko O.A.,Ukrainian Academy of Sciences | Fedorenko O.A.,State Key Laboratory of Molecular and Cellular Biology | Mamontov S.M.,Ukrainian Academy of Sciences | Kotik O.A.,Ukrainian Academy of Sciences | Talanov S.A.,Ukrainian Academy of Sciences
Neurophysiology | Year: 2014

At present, researchers are greatly interested in intracellular calcium signaling and, in particular, in the mechanisms of its disturbance in different pathologies. Nonetheless, rather limited information on the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the development of neurodegenerative processes has been accumulated. The aim of our study was to clarify whether the IP3R1 expression in neurons under conditions of experimental Parkinson's disease undergoes changes. In our experiments, we caused unilateral damage to dopaminergic neurons of the substantia nigra of rats using stereotaxic injections of 6-hydroxydopamine into the left ascending forebrain medial bundle (i.e., induced the state of experimental hemiparkinsonism). Using the technique of real-time polymerase chain reaction (RT PCR), we examined the level of expression of the itpr1 gene (that encodes type-1 IP3R subunits) in neurons of the cerebellum and motor cortex of intact rats and those with experimental hemiparkinsonism. In the latter animals, we observed higher levels of expression of gene itpr1 in neurons of both above-mentioned cerebral parts. In particular, the expression of this gene in the motor cortex exceeded that in the control rats more than two times, while in the cerebellum the excess was about 30 %. The higher expression of gene itpr1 in brain neurons can be a reason for abnormally intense release of Ca2+ from the cellular stores during the development of neurodegenerative processes. © 2014 Springer Science+Business Media New York.


Fedorenko O.A.,Bogomoletz Institute of Physiology | Fedorenko O.A.,State Key Laboratory of Molecular and Cellular Biology | Popugaeva E.,Saint Petersburg State Polytechnic University | Enomoto M.,University of Toronto | And 3 more authors.
European Journal of Pharmacology | Year: 2014

The inositol-1,4,5-trisphosphate receptors (InsP3Rs) are the major intracellular Ca2+-release channels in cells. Activity of InsP3Rs is essential for elementary and global Ca2+ events in the cell. There are three InsP3Rs isoforms that are present in mammalian cells. In this review we will focus primarily on InsP3R type 1. The InsP3R1 is a predominant isoform in neurons and it is the most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP3R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP3R-binding proteins. InsP3Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP3R1 play a role in a number of neurodegenerative disorders and other disease states. InsP3Rs represent a potentially valuable drug target for treatment of these disorders and for modulating activity of neurons and other cells. Future studies will provide better understanding of physiological functions of InsP3Rs in health and disease. © 2013 Elsevier B.V. All rights reserved.


Prevarskaya N.,French Institute of Health and Medical Research | Skryma R.,Lille University of Science and Technology | Shuba Y.,Ukrainian Academy of Sciences | Shuba Y.,State Key Laboratory of Molecular and Cellular Biology
Expert Opinion on Therapeutic Targets | Year: 2013

Introduction: Cancer is caused by defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to all of these phenomena, serving as major signalling agents with the spatial localisation, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. The transformation of a normal cell into a malignant derivative is associated with a major rearrangement of Ca2+ pumps, Na/Ca exchangers and Ca2+ channels, which leads to enhanced proliferation and invasion under compromised/impaired ability to die. Areas covered: This paper examines the changes in Ca2+ signalling and the mechanisms that underlie the passage from normal to pathological cell growth and death control. Understanding these changes and identifying the molecular players involved provide new perspectives for cancer treatment. Expert opinion: Despite compelling evidence that the disruption of Ca2+ homeostasis in cancer cells leads to the promotion of certain malignant phenotypes as well as the identification of key Ca2+-transporting molecules whose altered expression and/or function underlies pathological changes, the therapeutic utilisation of these findings for cancer treatment is still at its infancy. However, the rapid development of the field warrants the development of improved molecular Ca2+ transport-targeting tools for cancer diagnosis and treatment. © 2013 Informa UK, Ltd.


Prevarskaya N.,French Institute of Health and Medical Research | Prevarskaya N.,Lille University of Science and Technology | Ouadid-Ahidouch H.,Laboratory of Cellular and Molecular Physiology | Skryma R.,French Institute of Health and Medical Research | And 2 more authors.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca2+ signalling is determined by the concerted action of a molecular Ca2+handling toolkit which includes: active energy-dependent Ca2+ transporters, Ca2+-permeable ion channels, Ca2+-binding and storage proteins, Ca2+dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca2+-handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca2+ concentrations or spatio-temporal patterns of Ca2+ signalling become distorted. This causes deregulation of Ca2+dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca2+ homeostasis remodelling in cancer cells as well as in identification of the key Ca2+-transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca2+ transport-targeting tools for cancer diagnosis and treatment. © 2014 The Author(s) Published by the Royal Society.


Skorokhod O.,NASU Institute of Molecular Biology and Genetics | Skorokhod O.,State Key Laboratory of Molecular and Cellular Biology | Panasyuk G.,NASU Institute of Molecular Biology and Genetics | Nemazanyy I.,NASU Institute of Molecular Biology and Genetics | And 4 more authors.
Ukrain'skyi Biokhimichnyi Zhurnal | Year: 2013

Ribosomal protein S6 kinases (S6Ks) are principal regulators of cell size growth and metabolism. Signaling via the PI3K/mTOR pathway mediates the activation of S6Ks in response to various mitogenic stimuli, nutrients and stresses. To date, the regulation and cellular functions of S6Ks are not fully understood. Our aim was to investigate and characterize the interaction of S6Ks with the novel binding partner of S6Ks, Tudor domain containing 7 protein (TDRD7), which is a scaffold protein detected in complexes involved in the regulation of cytoskeleton dynamics, mRNA transport and translation, non-coding piRNAs processing and transposons silencing. This interaction was initially detected in the yeast two-hybrid screening of HeLa cDNA library and further confirmed by pull-down and co-immunoprecipitation assays. In addition we demonstrated that TDRD7 can form a complex with other isoform of S6K -S6K2. Notably, both isoforms of S6K were found to phosphorylate TDRD7 in vitro at multiple phosphorylation sites. Altogether, these findings demonstrate that TDRD7 is a novel substrate of S6Ks, suggesting the involvement of S6K signaling in the regulation of TDRD7 cellular functions.

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