Disease relevance of TRPM6

• Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family [1].
• Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg2+ excretion, and decreased serum Mg2+ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects [2].
• This hypothesis is strengthened by the identification of TRPM6 mutants in patients with a rare but severe hereditary disease called hypomagnesaemia with secondary hypocalcaemia [3].

High impact information on TRPM6

• TRPM6 is expressed in intestinal epithelia and kidney tubules [1].
• Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation [4].
• Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia [5].
• Full-length TRPM6 variants failed to form functional channel complexes because they were retained intracellularly on heterologous expression in HEK 293 cells and Xenopus oocytes [5].
• The naturally occurring S141L TRPM6 missense mutation abrogated the oligomeric assembly of TRPM6, thus providing a cell biological explanation for the human disease [5].

Chemical compound and disease context of TRPM6

• Identification of the gene defect in hypomagnesemia with secondary hypocalcemia recently elucidated transient receptor potential melastatin 6 (TRPM6) as the gatekeeper in transepithelial Mg(2+) transport, whereas its homolog, TRPM7, is implicated in cellular Mg(2+) homeostasis [6].

Biological context of TRPM6

• These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease [1].
• We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion [7].
• Amazingly, in analogy to TRPM6-deficient patients who can live a normal life if provided with a Mg(2+)-rich diet, TRPM7-deficient DT40 B-lymphocytes show wild type cell growth if supplied with 5-10 mm Mg(2+) concentrations in their extracellular medium [8].
• Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes [9].
• Genotype analysis revealed TRPM6 mutations in 37 of 42 expected mutant alleles [10].

Anatomical context of TRPM6

• Here, we show that TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and the brush-border membrane of the small intestine, epithelia particularly associated with active Mg2+ (re)absorption [11].
• This study demonstrates that TRPM6 is expressed predominantly in kidney, lung, cecum, and colon, whereas TRPM7 is distributed ubiquitously [6].
• The Mg(2+)-inhibited cation (MIC) current (I(MIC)) in cardiac myocytes biophysically resembles currents of heterologously expressed transient receptor potential (TRP) channels, particularly TRPM6 and TRPM7, known to be important in Mg(2+) homeostasis [12].
• In a lymphoblastoid cell line, derived from this patient, the normal X chromosome is preferentially inactivated, suggesting that the patient's phenotype is caused by disruption of an HSH gene in Xp22 [13].

Associations of TRPM6 with chemical compounds

• The TRPM6-induced channel displays strong outward rectification, has a 5-fold higher affinity for Mg2+ than for Ca2+, and is blocked in a voltage-dependent manner by ruthenium red [11].
• Our data demonstrate that TRPM6 requires TRPM7 for surface expression in HEK-293 cells and also that TRPM6 is capable of cross-phosphorylating TRPM7 as assessed using a phosphothreonine-specific antibody but not vice versa [8].
• The renal TRPM6 mRNA level in ovariectomized rats was significantly reduced, whereas 17beta-estradiol treatment normalized TRPM6 mRNA levels [6].
• In addition, TRPM6 and TRPM7 function as serine/threonine kinases with kinase domains at their C-terminal tails [3].
• TRP vanilloid 5 (TRPV5) is responsible for the rate-limiting Ca2+ entry, and TRP melastatin 6 (TRPM6) constitutes the apical entry step in Mg2+ reabsorption [14].

Regulatory relationships of TRPM6

• We show that TRPM7 deficiency in DT40 cells cannot be complemented by heterologously expressed TRPM6 [8].

Other interactions of TRPM6

• Together, our data suggest an important contribution of TRPM6/TRPM7 heterooligomerization for the biological role of TRPM6 in epithelial magnesium absorption [5].
• Reverse transcriptase-polymerase chain reaction revealed significant increases in messenger RNA abundance of transient potential receptor (TRP) V5 (223 +/- 10%), TRPV6 (177 +/- 9%), calbindin-D28k (231 +/- 8%), and TRPM6 (165 +/- 8%) in diabetic rats [15].

References