Background: A growing number of TRP channels have been identified as key players in the sensation of smell, temperature, mechanical forces and taste. TRPM5 is known to be abundantly expressed in taste receptor cells where it participates in sweet, amino acid and bitter perception. A role of TRPM5 in other sensory systems, however, has not been studied so far.

Hypomagnesemia with secondary hypocalcemia is an autosomal recessive disorder caused by mutations in the TRPM6 gene. Current experimental evidence suggests that TRPM6 may function in a specific association with TRPM7 by means of heterooligomeric channel complex formation. Here, we report the identification and functional characterization of a new hypomagnesemia with secondary hypocalcemia missense mutation in TRPM6. The affected subject presented with profound hypomagnesemia and hypocalcemia caused by compound heterozygous mutation in the TRPM6 gene: 1208(؊1)G > A affecting the acceptor splice site preceding exon 11, and 3050C > G resulting in the amino acid change (P1017R) in the putative pore-forming region of TRPM6. To assess the functional consequences of the P1017R mutation, TRPM6 P1017R and wild-type TRPM6 were co-expressed with TRPM7 in Xenopus oocytes and HEK 293 cells, and currents were assessed by two-electrode voltage clamp and whole cell patch clamp measurements, respectively. Co-expression of wild-type TRPM6 and TRPM7 resulted in a significant increase in the amplitude of TRPM7-like currents. In contrast, TRPM6 P1017R suppressed TRPM7 channel activity. In line with these observations, TRPM7, containing the corresponding mutation P1040R, displayed a dominant-negative effect upon co-expression with wild-type TRPM7. Confocal microscopy and fluorescence resonance energy transfer recordings demonstrated that the P1017R mutation neither affects assembly of TRPM6 with TRPM7, nor co-trafficking of heteromultimeric channel complexes to the cell surface. We conclude that a functional defect in the putative pore of TRPM6/7 channel complexes is sufficient to impair body magnesium homeostasis. Mg2ϩ plays a vital role in virtually all cellular pathways as a cofactor of enzymes, an essential structural element of proteins and nucleic acids, and a modulator of receptors and ion channels (1-4). At present, the molecular mechanisms controlling wasting (3, 9, 10). Hypocalcemia results from a secondary insufficiency of the parathyroid glands in the presence of profound hypomagnesemia. Supplementation with high Mg 2ϩ doses compensates for the Mg 2ϩ deficiency of HSH patients (3, 9, 10). TRPM6 belongs to the melastatin-related group of the TRP ion channel family (11,12). Like other TRP channels, TRPM proteins contain six transmembrane helices (S1-S6) flanked by cytoplasmic N and C termini; TRPMs most likely function as tetrameric channel complexes (12). Hydrophobic segments located between the S5 and S6 helices of four channel subunits are thought to contribute to a channel pore. In contrast to other known ion channels, TRPM6 and its closest family member, TRPM7, display the unique structural feature of being cation channels fused to Ser/Thr kinase domains at their C termini (13).TRPM7 is a ubiquitously expressed protein, which is essential for Mg 2ϩ homeostasis. Disruption of the TRPM7 gene in DT40 chicken lymphocytes and the zebrafish Danio rerio, resulted in Mg 2ϩ deficiency (14, 15). Functional characterization of he...