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10th International Congress "Cell Volume Regulation: Novel Therapeutic Targets and Pharmacological Approaches"
INTRACELLULAR MONOVALENT CATIONS AS REGULATORS OF CELL VOLUME AND GENE EXPRESSION
Orlov, S.N.
Laboratory of Physical Chemistry of Biological Membranes, M.V. Lomonosov Moscow State University, Moscow,
Russian Federation Research Centre, University of Montreal Hospital, Montreal, Canada
Cells respond to long-term exposure to anisosmotic environment by up- or down-regulation of the expression of gene products involved in the synthesis of compatible organic osmolytes. It is generally accepted that augmented transcription of these genes is caused by elevation of ionic strength, i.e. total intracellular concentrations of Na+, K+ and Cl-, that, in turn, leads to binding of the transcription factor tonicity enhancer binding protein (TonEBP otherwise known as NFAT5) with tonicity enhancer cis-element 1 [1]. Importantly, cell volume perturbations in isosmotic environment are caused by alteration of the [Na+]/[K+] ratio rather than ionic strength. Recently, we identified ubiquitous and tissue-specific [Na+]/[K+]r sensitive transcriptomes by comparative analysis of differentially expressed genes in vascular smooth muscle cells from rat aorta (RVSMC), the human adenocarcinoma cell line HeLa, and human umbilical vein endothelial cells (HUVEC) [2]. To augment [Na+] and reduce [K+]i, cells were treated for 3 hrs with the Na+,K+-ATPase inhibitor ouabain or placed for the same time in the K+-free medium. Among ubiquitous Na+i/K+i-sensitive genes we found
~2-fold increment of NFAT5 and up-to 10 fold elevation of expression of prostaglandin-endoperoxide synthase 2 (PTGS2) and cytochrome P450 CYP1A, i.e. genes that might be involved in cell volume regulation via PLA2-mediated pathways. Among cell-type specific genes involved in volume regulation of endothelial cells we found up to 3-fold elevation of RNA encoding P2Y2 purinergic receptors, ~2 fold attenuation of mRNA encoding catalytic subunits of PIP 5-kinase (PIP5K1C), up to 5-fold attenuation of regulatory subunits of PI-3-kinase PIK3R4 and PIK3R2, and 10-fold attenuation of expression of a negative regulator of PI-3 kinase activity PI-3-kinase interacting protein 1 (PIK3IP1). The role of these transcriptomic changes in cell volume regulation mediated by polyphosphoinositide signaling is currently investigated.
References
1. Burg, M.B., Ferraris, J.D., and Dmitrieva, N.I. 2007. Physiol. Rev., 87, pp. 1441-1474.
2. Koltsova, S.V., Trushina, Y., Haloui, M., Akimova, O.A., Tremblay, J., Hamet, P., and Orlov, S.N. 2012. PLoS One., 7, e38032.
Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24-68
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