TRPM6 and TRPM7 proteins share similar molecular structures and biophysical properties. Both proteins are Mg2+- and Ca2+-permeable cation channels with the typical topology of six transmembrane domains. In addition, TRPM6 and TRPM7 function as serine/threonine kinases with kinase domains at their C-terminal tails. At present, the role of the association of kinase and channel domains in TRPM6 and TRPM7 remains elusive. TRPM6 is mainly expressed in kidney and intestine, where it might be responsible for epithelial Mg2+ re/absorption. This hypothesis is strengthened by the identification of TRPM6 mutants in patients with a rare but severe hereditary disease called hypomagnesaemia with secondary hypocalcaemia. The aim of this review is to provide a brief but concise overview of the information currently available about TRPM6.


TRPM7 Transient receptor potential (TRP) channel Melastatin TRPM6 Magnesium absorption Hypomagnesaemia with secondary hypocalcaemia (HSH) 


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  1. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863–877PubMedCrossRefGoogle Scholar
  2. Abdulrazzaq YM, Smigura FC, Wettrell G (1989) Primary infantile hypomagnesaemia; report of two cases and review of literature. Eur J Pediatr 148:459–461PubMedCrossRefGoogle Scholar
  3. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedCrossRefGoogle Scholar
  4. Challa A, Papaefstathiou I, Lapatsanis D, Tsolas O (1995) Primary idiopathic hypomagnesemia in two female siblings. Acta Paediatr 84:1075–1078PubMedGoogle Scholar
  5. Chery M, Biancalana V, Philippe C, Malpuech G, Carla H, Gilgenkrantz S, Mandel JL, Hanauer A (1994) Hypomagnesemia with secondary hypocalcemia in a female with balanced X;9 translocation: mapping of the Xp22 chromosome breakpoint. Hum Genet 93:587–591PubMedCrossRefGoogle Scholar
  6. Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T (2004) Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci U S A 101:2894–2899PubMedCrossRefGoogle Scholar
  7. Chubanov V, Schlingmann KP, Waring J, Mederos y Schnitzler M, Waldegger S, Gudermann T (2006) Dominat-negativer Effekt einer neuen Missensmutation im menschlichen TRPM6-Gen führt zu Hypomagnesiämie mit sekundären Hypokalzämie. Naunyn Schmiedebergs Arch Pharmacol 372:60Google Scholar
  8. Dorovkov MV, Ryazanov AG (2004) Phosphorylation of annexin I by TRPM7 channel-kinase. J Biol Chem 279:50643–50646PubMedCrossRefGoogle Scholar
  9. Ehrlich BE, Kaftan E, Bezprozvannaya S, Bezprozvanny I (1994) The pharmacology of intracellular Ca2+-release channels. Trends Pharmacol Sci 15:145–149PubMedCrossRefGoogle Scholar
  10. Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ (2006) The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens. J Am Soc Nephrol 17:1035–1043PubMedCrossRefGoogle Scholar
  11. Gwanyanya A, Amuzescu B, Zakharov SI, Macianskiene R, Sipido KR, Bolotina VM, Vereecke J, Mubagwa K (2004) Magnesium-inhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. J Physiol 559:761–776PubMedGoogle Scholar
  12. Hanano T, Hara Y, Shi J, Morita H, Umebayashi C, Mori E, Sumimoto H, Ito Y, Mori Y, Inoue R (2004) Involvement of TRPM7 in cell growth as a spontaneously activated Ca2+ entry pathway in human retinoblastoma cells. J Pharmacol Sci 95:403–419PubMedCrossRefGoogle Scholar
  13. Hermosura MC, Monteilh-Zoller MK, Scharenberg AM, Penner R, Fleig A (2002) Dissociation of the store-operated calcium current I(CRAC) and the Mg-nucleotide-regulated metal ion current MagNuM. J Physiol 539:445–458PubMedCrossRefGoogle Scholar
  14. Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ (1999) Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274:8375–8378PubMedCrossRefGoogle Scholar
  15. Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ (2003) Homo-and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J 22:776–785PubMedCrossRefGoogle Scholar
  16. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, Zhu MX (2004) 2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J Biol Chem 279:35741–35748PubMedCrossRefGoogle Scholar
  17. Kayne LH, Lee DB (1993) Intestinal magnesium absorption. Miner Electrolyte Metab 19:210–217PubMedGoogle Scholar
  18. Konrad M, Weber S (2003) Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249–260PubMedCrossRefGoogle Scholar
  19. Kozak JA, Cahalan MD (2003) MIC channels are inhibited by internal divalent cations but not ATP. Biophys J 84:922–927PubMedCrossRefGoogle Scholar
  20. Kozak JA, Kerschbaum HH, Cahalan MD (2002) Distinct properties of CRAC and MIC channels in RBL cells. J Gen Physiol 120:221–235PubMedGoogle Scholar
  21. Lee CT, Lien YH, Lai LW, Chen JB, Lin CR, Chen HC (2006) Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus. Kidney Int 69:1786–1791PubMedCrossRefGoogle Scholar
  22. Luft JH (1971) Ruthenium red and violet. II. Fine structural localization in animal tissues. Anat Rec 171:369–415PubMedCrossRefGoogle Scholar
  23. Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K (1997) 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J Biochem (Tokyo) 122:498–505PubMedGoogle Scholar
  24. Meyer P, Boettger MB (2001) Familial hypomagnesaemia with secondary hypocalcaemia: a new case that indicates autosomal recessive inheritance. J Inherit Metab Dis 24:875–876PubMedCrossRefGoogle Scholar
  25. Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A (2001) LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 411:590–595PubMedCrossRefGoogle Scholar
  26. Nijenhuis T, Hoenderop JG, Bindels RJ (2004) Downregulation of Ca2+ and Mg2+ transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J Am Soc Nephrol 15:549–557PubMedCrossRefGoogle Scholar
  27. Nijenhuis T, Renkema KY, Hoenderop JG, Bindels RJ (2006) Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins. J Am Soc Nephrol 17:617–626PubMedCrossRefGoogle Scholar
  28. Nilius B, Prenen J, Vennekens R, Hoenderop JG, Bindels RJ, Droogmans G (2001) Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1. Br J Pharmacol 134:453–462PubMedCrossRefGoogle Scholar
  29. Nilius B, Prenen J, Droogmans G, Voets T, Vennekens R, Freichel M, Wissenbach U, Flockerzi V (2003) Voltage dependence of the Ca2+-activated cation channel TRPM4. J Biol Chem 278:30813–30820PubMedCrossRefGoogle Scholar
  30. Nilius B, Talavera K, Owsianik G, Prenen J, Droogmans G, Voets T (2005a) Gating of TRP channels: a voltage connection? J Physiol 567:35–44PubMedCrossRefGoogle Scholar
  31. Nilius B, Voets T, Peters J (2005b) TRP channels in disease. Sci STKE 2005:eg7Google Scholar
  32. Paunier L, Radde IC, Kooh SW, Conen PE, Fraser D (1968) Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 41:385–402PubMedGoogle Scholar
  33. Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA (1999) Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem 274:22739–22746PubMedCrossRefGoogle Scholar
  34. Perretti M, Solito E (2004) Annexin 1 and neutrophil apoptosis. Biochem Soc Trans 32:507–510PubMedCrossRefGoogle Scholar
  35. Prakriya M, Lewis RS (2002) Separation and characterization of currents through store-operated CRAC channels and Mg2+-inhibited cation (MIC) channels. J Gen Physiol 119:487–507PubMedCrossRefGoogle Scholar
  36. Pronicka E, Gruszczynska B (1991) Familial hypomagnesaemia with secondary hypocalcaemia-autosomal or X-linked inheritance? J Inherit Metab Dis 14:397–399PubMedCrossRefGoogle Scholar
  37. Riazanova LV, Pavur KS, Petrov AN, Dorovkov MV, Riazanov AG (2001) Novel type of signaling molecules: protein kinases covalently linked to ion channels (in Russian). Mol Biol (Mosk) 35:321–332Google Scholar
  38. Runnels LW, Yue L, Clapham DE (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291:1043–1047PubMedCrossRefGoogle Scholar
  39. Runnels LW, Yue L, Clapham DE (2002) The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat Cell Biol 4:329–336PubMedGoogle Scholar
  40. Ryazanova LV, Dorovkov MV, Ansari A, Ryazanov AG (2004) Characterization of the protein kinase activity of TRPM7/ChaK1, a protein kinase fused to the transient receptor potential ion channel. J Biol Chem 279:3708–3716PubMedCrossRefGoogle Scholar
  41. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170PubMedCrossRefGoogle Scholar
  42. Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM (2003) Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 114:191–200PubMedCrossRefGoogle Scholar
  43. Schweigel M, Martens H (2000) Magnesium transport in the gastrointestinal tract. Front Biosci 5:D666–D677PubMedGoogle Scholar
  44. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645–655PubMedCrossRefGoogle Scholar
  45. Talavera K, Yasumatsu K, Voets T, Droogmans G, Shigemura N, Ninomiya Y, Margolskee RF, Nilius B (2005) Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature 438:1022–1025PubMedCrossRefGoogle Scholar
  46. Visudhiphan P, Visudtibhan A, Chiemchanya S, Khongkhatithum C (2005) Neonatal seizures and familial hypomagnesemia with secondary hypocalcemia. Pediatr Neurol 33:202–205PubMedCrossRefGoogle Scholar
  47. Voets T, Prenen J, Vriens J, Watanabe H, Janssens A, Wissenbach U, Bödding M, Droogmans G, Nilius B (2002) Molecular determinants of permeation through the cation channel TRPV4. J Biol Chem 277:33704–33710PubMedCrossRefGoogle Scholar
  48. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279:19–25PubMedCrossRefGoogle Scholar
  49. Walder RY, Shalev H, Brennan TM, Carmi R, Elbedour K, Scott DA, Hanauer A, Mark AL, Patil S, Stone EM, Sheffield VC (1997) Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint. Hum Mol Genet 6:1491–1497PubMedCrossRefGoogle Scholar
  50. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31:171–174PubMedCrossRefGoogle Scholar
  51. Wu SN, Jan CR, Li HF (1999) Ruthenium red-mediated inhibition of large-conductance Ca2+-activated K+ channels in rat pituitary GH3 cells. J Pharmacol Exp Ther 290:998–1005PubMedGoogle Scholar
  52. Xu SZ, Zeng F, Boulay G, Grimm C, Harteneck C, Beech DJ (2005) Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol 145:405–414PubMedCrossRefGoogle Scholar
  53. Yamaguchi H, Matsushita M, Nairn AC, Kuriyan J (2001) Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 7:1047–1057PubMedCrossRefGoogle Scholar
  54. Yamamoto T, Kabata H, Yagi R, Takashima M, Itokawa Y (1985) Primary hypomagnesemia with secondary hypocalcemia. Report of a case and review of the world literature. Magnesium 4:153–164PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • M. Bödding
    • 1
  1. 1.Experimentelle und Klinische Pharmakologie und ToxikologieUniversität des SaarlandesHomburgGermany

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