nesium (Mg 2ϩ ) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

Ca(2+) is an essential ion in all organisms, where it plays a crucial role in processes ranging from the formation and maintenance of the skeleton to the temporal and spatial regulation of neuronal function. The Ca(2+) balance is maintained by the concerted action of three organ systems, including the gastrointestinal tract, bone, and kidney. An adult ingests on average 1 g Ca(2+) daily from which 0.35 g is absorbed in the small intestine by a mechanism that is controlled primarily by the calciotropic hormones. To maintain the Ca(2+) balance, the kidney must excrete the same amount of Ca(2+) that the small intestine absorbs. This is accomplished by a combination of filtration of Ca(2+) across the glomeruli and subsequent reabsorption of the filtered Ca(2+) along the renal tubules. Bone turnover is a continuous process involving both resorption of existing bone and deposition of new bone. The above-mentioned Ca(2+) fluxes are stimulated by the synergistic actions of active vitamin D (1,25-dihydroxyvitamin D(3)) and parathyroid hormone. Until recently, the mechanism by which Ca(2+) enter the absorptive epithelia was unknown. A major breakthrough in completing the molecular details of these pathways was the identification of the epithelial Ca(2+) channel family consisting of two members: TRPV5 and TRPV6. Functional analysis indicated that these Ca(2+) channels constitute the rate-limiting step in Ca(2+)-transporting epithelia. They form the prime target for hormonal control of the active Ca(2+) flux from the intestinal lumen or urine space to the blood compartment. This review describes the characteristics of epithelial Ca(2+) transport in general and highlights in particular the distinctive features and the physiological relevance of the new epithelial Ca(2+) channels accumulating in a comprehensive model for epithelial Ca(2+) absorption.

Mg2؉ is an essential ion involved in a multitude of physiological and biochemical processes and a major constituent of bone tissue. Recently, a positional candidate screening approach in consanguineous families with hypomagnesemia with secondary hypocalcemia (HSH) revealed a critical region identified on chromosome 9q21.13 (2, 3). Individuals suffering from HSH display neurologic symptoms including seizures and tetany during infancy. These symptoms can be suppressed by life-long dietary magnesium supplementation, but, untreated, the disease may be fatal or result in neurological damage. The pathophysiology of HSH is largely unknown, but physiological studies have shown that there are defects in both intestinal Mg 2ϩ absorption and renal Mg 2ϩ reabsorption. Subsequent analysis of the critical region pointed to a gene, TRPM6, which was mutated in patients with HSH (2, 3). The TRPM6 protein is a member of the transient receptor potential channel (TRP) family (4).Based on the structural and sequence similarities between individual TRP proteins, three subgroups are distinguished, namely the canonical TRPC-, the vanilloid-like TRPV-, and the melastatin-like TRPM subfamilies. Most members of the TRPC-and TRPV-subfamilies have been characterized as Ca 2ϩ -permeable cation channels playing a role in Ca 2ϩ homeostasis and signaling (4). However, the functional characterization of TRPM proteins is much more incomplete. TRPM6 shows 50% sequence homology with TRPM7 (also known as TRP-PLIK), which forms a Ca 2ϩ and Mg 2ϩ -permeable cation channel. Unlike other members of the TRP family, TRPM6 and TRPM7 contain long carboxyl-terminal domains with similarity to the ␣-kinases (5). The identification of TRPM6 as the gene mutated in HSH represents the first case in which a human disorder has been attributed to a channel kinase.The aim of the present study was to functionally characterize TRPM6 as the first molecularly identified protein involved in active Mg 2ϩ (re)absorption. To this end, the (sub)localization of TRPM6 was investigated by immunohistochemical analysis of kidney and duodenum sections. Subsequently, human TRPM6 cDNA was cloned, transfected into human embryonic kidney

Blood calcium concentration is maintained within a narrow range despite large variations in dietary input and body demand. The Transient Receptor Potential ion channel TRPV5 has been implicated in this process. We report here that TRPV5 is stimulated by the mammalian hormone klotho. Klotho, a beta-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane. This maintains durable calcium channel activity and membrane calcium permeability in kidney. Thus, klotho activates a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides.

Rickets and hyperparathyroidism caused by a defective vitamin D receptor (VDR) can be prevented in humans and animals by high calcium intake, suggesting that intestinal calcium absorption is critical for 1,25(OH) 2 vitamin D [1,25(OH)2D3] action on calcium homeostasis. We assessed the rate of serum 45 Ca accumulation within 10 min of oral gavage in two strains of VDR-knockout (KO) mice (Leuven and Tokyo KO) and observed a 3-fold lower area under the curve in both KO strains. Moreover, we evaluated the expression of intestinal candidate genes involved in transcellular calcium transport. The calcium transport protein1 (CaT1) was more abundantly expressed at mRNA level than the epithelial calcium channel (ECaC) in duodenum, but both were considerably reduced (CaT1>90%, ECaC>60%) in the two VDR-KO strains on a normal calcium diet. Calbindin-D 9K expression was decreased only in the Tokyo KO, whereas plasma membrane calcium ATPase (PMCA 1b) expression was normal in both VDR-KOs. In Leuven wild-type mice, a high calcium diet inhibited (>90%) and 1,25(OH) 2D3 injection or low calcium diet induced (6-fold) duodenal CaT1 expression and, to a lesser degree, ECaC and calbindin-D 9K expression. In Leuven KO mice, however, high or low calcium intake decreased calbindin-D 9K and PMCA1b expression, whereas CaT1 and ECaC expression remained consistently low on any diet. These results suggest that the expression of the novel duodenal epithelial calcium channels (in particular CaT1) is strongly vitamin D-dependent, and that calcium influx, probably interacting with calbindin-D 9K, should be considered as a rate-limiting step in the process of vitamin D-dependent active calcium absorption.