Magnesium Abstracts 3 - Transport

© 2012

Mechanisms of magnesium transport

            (Flatman 1991) Download

Magnesium ions and ionic channels: activation, inhibition or block--a hypothesis

            (Guiet-Bara, Durlach et al. 2007) Download

The interactions between magnesium ions and ionic membrane channels are complicated and may be classified in three categories: activation, reduction and inhibition of the ionic fluxes across the channels, corresponding to three mechanisms: open-block-close. The interactions between magnesium ions and various ionic channels are reviewed and the explanations of the three mechanisms are analyzed in term of screening/binding effects on the membrane surface polar head groups.

Mechanisms, regulation and pathologic significance of Mg2+ efflux from erythrocytes

            (Gunther 2006) Download

Mg2+ efflux from erythrocytes can be performed by the Na+/Mg2+ antiport and by Na+-independent Mg2+ efflux. Na+-independent Mg2+ efflux functions via the unspecific choline exchanger as choline/Mg2+ or K+/Mg2+ antiport and as Mg2+ efflux accompanied by intracellular Cl- for charge compensation, as found for example in sucrose medium. Na+/Mg2+ antiport in erythrocytes exchanges 2 extracellular Na+ for 1 intracellular Mg2+. Driving forces are the Na+ and Mg2+ gradients. By reversing these gradients, the Na+/Mg2+ antiporter can mediate Mg2+ influx. The Na+/Mg2+ antiporter can exchange 24Mg2+ for 28Mg2+ and other divalent cations for intracellular Mg2+. In the exchange mechanism, extra- and intracellular Na+ can compete with Mg2+. Na+/Mg2+ antiport is inhibited by amiloride, quinidine and imipramine. Na+/Mg2+ antiport is drastically activated by intracellular Mg2+ due to an allosteric transition. The affinity of intracellular Mg2+ to the Na+/Mg2+ antiporter is dependent on intracellular ATP due to phosphorylation. Besides this mechanism, in non Mg2+-loaded erythrocytes, the activity of Na+/Mg2+ antiport is regulated by phosphorylation-dephosphorylation and by intracellular Cl-. The drastically Mg2+-activated Na+/Mg2+ antiporter is not further stimulated by phosphorylation and intracellular Cl-. Na+-independent Mg2+ efflux via the choline exchanger is also inhibited by amiloride, quinidine and imipramine, and can also be regulated by phosphorylation-dephosphorylation. Na+/Mg2+ antiport of erythrocytes is altered in various pathologic conditions.

Human gene SLC41A1 encodes for the Na+/Mg(2)+ exchanger

            (Kolisek, Nestler et al. 2012) Download

Magnesium (Mg(2+)), the second most abundant divalent intracellular cation, is involved in the vast majority of intracellular processes, including the synthesis of nucleic acids, proteins, and energy metabolism. The concentration of intracellular free Mg(2+) ([Mg(2+)](i)) in mammalian cells is therefore tightly regulated to its optimum, mainly by an exchange of intracellular Mg(2+) for extracellular Na(+). Despite the importance of this process for cellular Mg(2+) homeostasis, the gene(s) encoding for the functional Na(+)/Mg(2+) exchanger is (are) still unknown. Here, using the fluorescent probe mag-fura 2 to measure [Mg(2+)](i) changes, we examine Mg(2+) extrusion from hSLC41A1-overexpressing human embryonic kidney (HEK)-293 cells. A three- to fourfold elevation of [Mg(2+)](i) was accompanied by a five- to ninefold increase of Mg(2+) efflux. The latter was strictly dependent on extracellular Na(+) and reduced by 91% after complete replacement of Na(+) with N-methyl-d-glucamine. Imipramine and quinidine, known unspecific Na(+)/Mg(2+) exchanger inhibitors, led to a strong 88% to 100% inhibition of hSLC41A1-related Mg(2+) extrusion. In addition, our data show regulation of the transport activity via phosphorylation by cAMP-dependent protein kinase A. As these are the typical characteristics of a Na(+)/Mg(2+) exchanger, we conclude that the human SLC41A1 gene encodes for the Na(+)/Mg(2+) exchanger, the predominant Mg(2+) efflux system. Based on this finding, the analysis of Na(+)/Mg(2+) exchanger regulation and its involvement in the pathogenesis of diseases such as Parkinson's disease and hypertension at the molecular level should now be possible.

Regulation of Alr1 Mg transporter activity by intracellular magnesium

            (Lim, Pisat et al. 2011) Download

Mg homeostasis is critical to eukaryotic cells, but the contribution of Mg transporter activity to homeostasis is not fully understood. In yeast, Mg uptake is primarily mediated by the Alr1 transporter, which also allows low affinity uptake of other divalent cations such as Ni(2+), Mn(2+), Zn(2+) and Co(2+). Using Ni(2+) uptake to assay Alr1 activity, we observed approximately nine-fold more activity under Mg-deficient conditions. The mnr2 mutation, which is thought to block release of vacuolar Mg stores, was associated with increased Alr1 activity, suggesting Alr1 was regulated by intracellular Mg supply. Consistent with a previous report of the regulation of Alr1 expression by Mg supply, Mg deficiency and the mnr2 mutation both increased the accumulation of a carboxy-terminal epitope-tagged version of the Alr1 protein (Alr1-HA). However, Mg supply had little effect on ALR1 promoter activity or mRNA levels. In addition, while Mg deficiency caused a seven-fold increase in Alr1-HA accumulation, the N-terminally tagged and untagged Alr1 proteins increased less than two-fold. These observations argue that the Mg-dependent accumulation of the C-terminal epitope-tagged protein was primarily an artifact of its modification. Plasma membrane localization of YFP-tagged Alr1 was also unaffected by Mg supply, indicating that a change in Alr1 location did not explain the increased activity we observed. We conclude that variation in Alr1 protein accumulation or location does not make a substantial contribution to its regulation by Mg supply, suggesting Alr1 activity is directly regulated via as yet unknown mechanisms.

Magnesium transport in hypertension

         (Sontia and Touyz 2007) Download

Epidemiological, clinical and experimental evidence indicates an inverse association between Mg(2+) levels (serum and tissue) and blood pressure. Magnesium may influence blood pressure by modulating vascular tone and structure through its effects on numerous biochemical reactions that control vascular contraction/dilation, growth/apoptosis, differentiation and inflammation. Magnesium acts as a calcium channel antagonist, it stimulates production of vasodilator prostacyclins and nitric oxide and it alters vascular responses to vasoactive agonists. Mammalian cells regulate Mg(2+) concentration through specialized influx and efflux transport systems that have only recently been characterized. Magnesium efflux occurs via Na(2+)-dependent and Na(2+)-independent pathways. Mg(2+) influx is controlled by recently cloned transporters including Mrs2p, SLC41A1, SLC41A1, ACDP2, MagT1, TRPM6 and TRPM7. Alterations in some of these systems may contribute to hypomagnesemia and intracellular Mg(2+) deficiency in hypertension. In particular increased Mg(2+) efflux through altered regulation of the vascular Na(+)/Mg(2+) exchanger and decreased Mg(2+) influx due to defective vascular and renal TRPM6/7 expression/activity may be important. This review discusses the role of Mg(2+) in vascular biology and implications in hypertension and focuses on the putative transport systems that control vascular magnesium homeostasis. Much research is still needed to clarify the exact mechanisms of Mg(2+) regulation in the cardiovascular system and the implications of aberrant transcellular Mg(2+) transport in the pathogenesis of cardiovascular disease.


References

Flatman, P. W. (1991). "Mechanisms of magnesium transport." Annu Rev Physiol 53: 259-71.

Guiet-Bara, A., J. Durlach, et al. (2007). "Magnesium ions and ionic channels: activation, inhibition or block--a hypothesis." Magnes Res 20(2): 100-6.

Gunther, T. (2006). "Mechanisms, regulation and pathologic significance of Mg2+ efflux from erythrocytes." Magnes Res 19(3): 190-8.

Kolisek, M., A. Nestler, et al. (2012). "Human gene SLC41A1 encodes for the Na+/Mg(2)+ exchanger." Am J Physiol Cell Physiol 302(1): C318-26.

Lim, P. H., N. P. Pisat, et al. (2011). "Regulation of Alr1 Mg transporter activity by intracellular magnesium." PLoS One 6(6): e20896.

Sontia, B. and R. M. Touyz (2007). "Magnesium transport in hypertension." Pathophysiology 14(3-4): 205-11.