Augmented gene expression triggered by Na+, K+-ATPase inhibition: Role of Ca2+i-mediated and −independent excitation-transcription coupling. (December 2017)

• Record Type: Journal Article
• Authors: Smolyaninova, Larisa V.; Koltsova, Svetlana V.; Sidorenko, Svetlana V.; Orlov, Sergei N.
• Is Part Of: Cell calcium. Volume 68(2017)
• Page Start: 5
• Page End: 13
• Publication Date: 2017-12
• Subjects: Sodium -- Potassium -- Calcium -- Egr1 -- Atf3 -- Nr4a1 -- Ptgs2 -- Excitation-transcription coupling; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2017.10.002
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Na +, K + -ATPase inhibition sharply increased expression of Egr1, Atf3, Nr4a1 and Ptgs2 . Na +, K + -ATPase inhibition increased Ca 2+ influx via L-type channels. Inhibition of Ca2+-dependent protein kinase CaMKII suppressed Ptgs2 expression. Inhibition of Ca2+-dependent phosphatase calcineurin suppressed Nr4a1 expression. Augmented expression of Egr1 and Atf3 is mediated by Ca2 + i-independent signalling. Abstract: In rat vascular smooth muscle cells (RVSMC), 3-h Na +, K + -ATPase inhibition by ouabain or in K + -free medium resulted in the inversion of the [Na + ]i /[K + ]i ratio and elevation up to 7-fold the content of Egr1, Atf3, Nr4a1 and Ptgs2 mRNAs. Ouabain increased the rate of 45Ca 2+ influx by 2-fold that was abolished by L-type voltage-gated Ca 2+ channel blocker nicardipine, but it was resistant to Na + /Ca 2+ exchanger inhibitor KB-R7943. To study the role of Ca 2+ -mediated signaling in the expression of Na + i /K + i -sensitive genes we used intracellular Ca 2+ chelator BAPTA and incubated RVSMC in Ca 2+ -free medium. The elevation of Nr4a1 and Ptgs2 expression triggered by ouabain was diminished in Ca 2+ -depeleted cells as well as in the presence of nicardipine and calmodulin antagonists A-7 and W-7. Ptgs2 expression was also suppressed by inhibitor of Ca 2+ /calmodulin-dependent protein kinase (CaMKII) KN-93 whereas increment of Nr4a1 content triggered by ouabain was attenuated by inhibitor of Ca 2+ /calmodulin-dependent protein phosphatase (calcineurin, CaN) cyclosporin A. Neither Ca 2+ depletion nor above listed compounds had any impact on the augmented expression of Egr1 and Atf3 in ouabain-treated RVSMC. Our results strongly suggest that dissipation of transmembrane gradient of monovalent cations increases Ptgs2 and Nr4a1 transcription via augment Ca 2+ influx through L-type Ca 2+ channels that, in turn, leads to CaMKII-mediated phosphorylation of CREB and calcineurin-mediated dephosphorylation of NFAT, respectively. Additional experiments should be performed to identify intermediates of Na + i, K + i -mediated Ca 2+ -independent excitation-transcription coupling involved the regulation of Egr1 and Atf3 expression.