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The unique nature of mg2+ channels.

ABSTRACT: Considering the biological abundance and importance of Mg2+, there is a surprising lack of information regarding the proteins that transport Mg2+, the mechanisms by which they do so, and their physiological roles within the cell. The best characterized Mg2+ channel to date is the bacterial protein CorA, present in a wide range of bacterial species. The CorA homolog Mrs2 forms the mitochondrial Mg2+ channel in all eukaryotes. Physiologically, CorA is involved in bacterial pathogenesis, and the Mrs2 eukaryotic homolog is essential for cell survival. A second Mg2+ channel widespread in bacteria is MgtE. Its eukaryotic homologs are the SLC41 family of carriers. Physiological roles for MgtE and its homologs have not been established. Recently, the crystal structures for the bacterial CorA and MgtE Mg2+ channels were solved, the first structures of any divalent cation channel. As befits the unique biological chemistry of Mg2+, both structures are unique, unlike that of any other channel or transporter. Although structurally quite different, both CorA and MgtE appear to be gated in a similar manner through multiple Mg2+ binding sites in the cytosolic domain of the channels. These sites essentially serve as Mg2+ "sensors" of cytosolic Mg2+ concentration. Many questions about these channels remain, however, including the molecular basis of Mg2+ selectivity and the physiological role(s) of their eukaryotic homologs.

SUBMITTER: Moomaw AS

PROVIDER: S-EPMC2711038 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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The unique nature of mg2+ channels.

Moomaw Andrea S AS Maguire Michael E ME

Physiology (Bethesda, Md.) 20081001

Considering the biological abundance and importance of Mg2+, there is a surprising lack of information regarding the proteins that transport Mg2+, the mechanisms by which they do so, and their physiological roles within the cell. The best characterized Mg2+ channel to date is the bacterial protein CorA, present in a wide range of bacterial species. The CorA homolog Mrs2 forms the mitochondrial Mg2+ channel in all eukaryotes. Physiologically, CorA is involved in bacterial pathogenesis, and the Mr ...[more]

PMID: 18927203

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Project description:Magnesium levels in cardiac myocytes change in cardiovascular diseases. Intracellular free magnesium (Mg(i)) inhibits L-type Ca(2+) currents through Ca(V)1.2 channels in cardiac myocytes, but the mechanism of this effect is unknown. We hypothesized that Mg(i) acts through the COOH-terminal EF-hand of Ca(V)1.2. EF-hand mutants were engineered to have either decreased (D1546A/N/S/K) or increased (K1543D and K1539D) Mg(2+) affinity. In whole-cell patch clamp experiments, increased Mg(i) reduced both Ba(2+) and Ca(2+) currents conducted by wild type (WT) Ca(V)1.2 channels expressed in tsA-201 cells with similar affinity. Exposure of WT Ca(V)1.2 to lower Mg(i) (0.26 mM) increased the amplitudes of Ba(2+) currents 2.6 +/- 0.4-fold without effects on the voltage dependence of activation and inactivation. In contrast, increasing Mg(i) to 2.4 or 7.2 mM reduced current amplitude to 0.5 +/- 0.1 and 0.26 +/- 0.05 of the control level at 0.8 mM Mg(i). The effects of Mg(i) on peak Ba(2+) currents were approximately fit by a single binding site model with an apparent K(d) of 0.65 mM. The apparent K(d) for this effect of Mg(i) was shifted approximately 3.3- to 16.5-fold to higher concentration in D1546A/N/S mutants, with only small effects on the voltage dependence of activation and inactivation. Moreover, mutant D1546K was insensitive to Mg(i) up to 7.2 mM. In contrast to these results, peak Ba(2+) currents through the K1543D mutant were inhibited by lower concentrations of Mg(i) compared with WT, consistent with approximately fourfold reduction in apparent K(d) for Mg(i), and inhibition of mutant K1539D by Mg(i) was also increased comparably. In addition to these effects, voltage-dependent inactivation of K1543D and K1539D was incomplete at positive membrane potentials when Mg(i) was reduced to 0.26 or 0.1 mM, respectively. These results support a novel mechanism linking the COOH-terminal EF-hand with modulation of Ca(V)1.2 channels by Mg(i). Our findings expand the repertoire of modulatory interactions taking place at the COOH terminus of Ca(V)1.2 channels, and reveal a potentially important role of Mg(i) binding to the COOH-terminal EF-hand in regulating Ca(2+) influx in physiological and pathophysiological states.

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The unique nature of mg2+ channels.

Publications

The unique nature of mg2+ channels.

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