Research Papers:

Overexpression of Na+/Mg2+ exchanger SLC41A1 attenuates pro-survival signaling

Gerhard Sponder, Nasrin Abdulhanan, Nadine Fröhlich, Lucia Mastrototaro, Jörg R. Aschenbach, Monika Röntgen, Ivana Pilchova, Michal Cibulka, Peter Racay and Martin Kolisek _

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Oncotarget. 2018; 9:5084-5104. https://doi.org/10.18632/oncotarget.23598

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Gerhard Sponder1, Nasrin Abdulhanan1,*, Nadine Fröhlich2, Lucia Mastrototaro1, Jörg R. Aschenbach1, Monika Röntgen3, Ivana Pilchova4, Michal Cibulka5, Peter Racay4,5 and Martin Kolisek1,4,*

1Institute of Veterinary-Physiology, Free University of Berlin, Berlin, Germany

2PerkinElmer Life and Analytical Sciences GmbH, Rodgau, Germany

3Leibnitz Institute for Farm Animal Biology, Department of Muscle and Growth Physiology, Dummerstorf, Germany

4Biomedical Center Martin, Division of Neurosciences, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia

5Institute of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia

*Present/Current address: bess pro GmbH, Berlin, Germany

Correspondence to:

Martin Kolisek, email: [email protected]

Keywords: Na+/Mg2+ exchanger; Mg2+ homeostasis; Akt/PKB; dynamic mass redistribution; signaling

Received: February 17, 2017     Accepted: November 13, 2017     Published: December 22, 2017


The Na+/Mg2+ exchanger SLC41A1 (A1), a key component of intracellular Mg homeostasis (IMH), is the major cellular Mg2+ efflux system, and its overexpression decreases [Mg2+]intracellular. IMH plays an important role in the regulation of many cellular processes, including cellular signaling. However, whether the overexpression of A1 and the consequent drop of [Mg2+]i impact on intracellular signaling is unknown.

To examine the latter, we utilized dynamic mass redistribution (DMR) assay, PathScan® RTK signaling antibody (PRSA) array, confirmatory Western blot (WB) analyses of phosphorylation of kinases selected by PRSA, and mag-fura 2-assisted fast filter spectrometry (FFS).

We demonstrate here that the overexpression of A1 quantitatively and qualitatively changes the DMR signal evoked by the application of PAR-1-selective activating peptide and/or by changing [Mg2+]extracellular in HEK293 cells. PRSA profiling of the phosphorylation of important signaling nodes followed by confirmatory WB has revealed that, in HEK293 cells, A1 overexpression significantly attenuates the phosphorylation of Akt/PKB on Thr308 and/or Ser473 and of Erk1/2 on Thr202/Tyr204 in the presence of 0 or 1 mM (physiological) Mg2+ in the bath solution. The latter is also true for SH-SY5Y and HeLa cells. Overexpression of A1 in HEK293 cells significantly lowers [Mg2+]i in the presence of [Mg2+]e = 0 or 1 mM. This correlates with the observed attenuation of prosurvival Akt/PKB – Erk1/2 signaling in these cells.

Thus, A1 expression status and [Mg2+]e (and consequently also [Mg2+]i) modulate the complex physiological fingerprint of the cell and influence the activity of kinases involved in anti-apoptotic and, hence, pro-survival events in cells.

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