TRPM6 and TRPM7—Gatekeepers of human magnesium metabolism

Abstract

Human magnesium homeostasis primarily depends on the balance between intestinal absorption and renal excretion. Magnesium transport processes in both organ systems - next to passive paracellular magnesium flux - involve active transcellular magnesium transport consisting of an apical uptake into the epithelial cell and a basolateral extrusion into the interstitium. Whereas the mechanism of basolateral magnesium extrusion remains unknown, recent molecular genetic studies in patients with hereditary hypomagnesemia helped gain insight into the molecular nature of apical magnesium entry into intestinal brush border and renal tubular epithelial cells. Patients with Hypomagnesemia with Secondary Hypocalcemia (HSH), a primary defect in intestinal magnesium absorption, were found to carry mutations in TRPM6, a member of the melastatin-related subfamily of transient receptor potential (TRP) ion channels. Before, a close homologue of TRPM6, TRPM7, had been characterized as a magnesium and calcium permeable ion channel vital for cellular magnesium homeostasis. Both proteins share the unique feature of an ion channel fused to a kinase domain with homology to the family of atypical alpha kinases. The aim of this review is to summarize the data emerging from clinical and molecular genetic studies as well as from electrophysiologic and biochemical studies on these fascinating two new proteins and their role in human magnesium metabolism.

Environmental factors responsible for switching on the SO42−excretory system in the kidney of seawater eels

“…Because of the huge difference in Mg 2ϩ concentration between plasma and SW, Mg 2ϩ regulation at the kidney is also thought to be altered by the environmental salinity in fishes (2,4). Recently, transient receptor potential melastatin type channels (TRPM6 and 7) were found to be involved in the Mg 2ϩ reabsorption in the distal convoluted tubule of mammals (30). The TRP channels may act also as a sensor because TRP vanilloid type channels (TRPV2 and 4) are shown to be an osmosensor for regulation of thirst and vasopressin secretion (31).…”

TRP Channels and Pruritus

“…cellular homeostasis of different ions, secretory mechanisms, sensory functions of the nervous system, inflammation, etc.) [155][156][157][158][159][160]. In addition, they exert fundamental influence on cell-fate as they regulate differentiation and proliferation of different cell types [161][162][163].…”

Magnesium in the Central Nervous System

“…Although one cannot dismiss the possibility that new channels may be involved in the transport of magnesium at the choroid plexus, it is natural to look at other systems for similar magnesium transport mechanisms. As stated above the strongest evidence for magnesium transport was obtained from genetic studies in familial hypomagnesemia, positional cloning and knockout mice investigations (Konrad et al, 2006;Schlingmann et al, 2007;Walder et al, 2002) which identified TRPM6 and TRPM7 as candidates for transcellular transport, and Claudin16 (Efrati et al, 2005; for paracellular transport in the kidney. Recently TRPM7 has also been identified in smooth muscle cells in the vasculature (Callera et al, 2009).…”

“…In fact, decreased extracellular magnesium availability does not necessarily reflect an intracellular depletion, as demonstrated by the fact that in vivo serum magnesium levels are not a reliable marker of pathological hypo--magnesemia. Sensitivity to extracellular magnesium availability is highly tissue--specific, and can be translated in molecular terms by considering the expression and activity of magnesium--specific cation channels, such as the transient receptor potential melastatin (TRPM) --6 and --7 channels, which, by modulating trans--membrane cation fluxes, regulate the intracellular ion concentration (Schlingmann et al, 2007). Furthermore, intracellular magnesium is tightly buffered to meet specific metabolic requirements.…”

“…Immortalized mouse brain microvessel endo--thelial cells, freshly isolated cerebral microvessels and primary cultured rat brain endothelial cells express multiple TRPC and TRPV isoforms, and also TRPM2, M3, M4, and M7 mRNA (Brown et al, 2008). We would like to suggest therefore that the TRPM6 and TRPM7, the gatekeepers of magnesium (Schlingmann et al, 2007), are likely to play a main role in brain endothelial cell transport of magnesium via the transcellular route. Western blotting and immunofluorescence assays for TRPM6 and TRPM7 similar to those performed for TRPV4 in mouse cerebral microvascular endothelial cells would support this suggestion.…”