Human gene SLC41A1 encodes for the Na⁺/Mg²⁺ exchanger

Abstract

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.

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

“…The absorbed magnesium is then extruded via a recently identified magnesium/sodium exchanger SLC41A1 family (89)(90)(91)(92) across the basolateral membrane (93). Interestingly, mutations in SLC41A1 result in a nephronophthisis-like phenotype (93).…”

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

“…SLC41A1, a member of the solute carrier family 41, is a cell membrane protein expressed in various tissues, including heart, brain, kidney, liver, and colon, and has been proposed as one of the candidates for such Mg 2+ transporters. [28][29][30] Although Mg 2+ transport by SLC41A1 has not been fully characterized, Kolisek et al recently reported that the human SLC41A1 gene encodes for the Na + /Mg 2+ exchanger 4. 28 The finding that mutations of this renal Mg 2+ transporter mimics an NPHP-RC phenotype may be related to the fact that other mutations in proteins involved in renal Mg 2+ transport are known to cause an NPHP-related disorder phenotype.…”

“…[28][29][30] Although Mg 2+ transport by SLC41A1 has not been fully characterized, Kolisek et al recently reported that the human SLC41A1 gene encodes for the Na + /Mg 2+ exchanger 4. 28 The finding that mutations of this renal Mg 2+ transporter mimics an NPHP-RC phenotype may be related to the fact that other mutations in proteins involved in renal Mg 2+ transport are known to cause an NPHP-related disorder phenotype. Specifically, recessive mutations of the CLDN16 gene encoding the renal tight junction protein claudin-16 (also called paracellin-1) cause a recessive renal disease that closely mimics NPHP 31 in cattle 24 both clinically and histologically.…”

Juvenile nephronophthisis and dysthyroidism: a rare association

“…Although hypomagnesemia occasionally complicates nonoliguric acute tubular necrosis associated with nephrotoxic drugs, but hypokalemia is accompanied with these conditions. Recently Kolisek et al has reported that the human solute carrier family 41, anion exchanger, member 1[SLC41A1 (mapped on chromosome 1q 31-32)] encodes for the Na + /Mg 2+ exchanger 4 [13] and gain of function mutation of SLC41A1 is associated with Parkinson's disease [14]. But in study by hurd et al, whole-exome capture revealed a homozygous splice acceptor site mutation in the renal Mg 2+ transporter SLC41A1.…”