Skip to main content

TRPM6: A Janus-Like Protein

  • Chapter

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 179))

Abstract

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.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   429.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   549.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • 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 115:863–877

    Article  CAS  PubMed  Google Scholar 

  • Abdulrazzaq YM, Smigura FC, Wettrell G (1989) Primary infantile hypomagnesaemia; report of two cases and review of literature. Eur J Pediatr 148:459–461

    Article  CAS  PubMed  Google Scholar 

  • 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 389:816–824

    Article  CAS  PubMed  Google Scholar 

  • Challa A, Papaefstathiou I, Lapatsanis D, Tsolas O (1995) Primary idiopathic hypomagnesemia in two female siblings. Acta Paediatr 84:1075–1078

    CAS  PubMed  Google Scholar 

  • 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 93:587–591

    Article  CAS  PubMed  Google Scholar 

  • 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 101:2894–2899

    Article  CAS  PubMed  Google Scholar 

  • 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 372:60

    Google Scholar 

  • Dorovkov MV, Ryazanov AG (2004) Phosphorylation of annexin I by TRPM7 channel-kinase. J Biol Chem 279:50643–50646

    Article  CAS  PubMed  Google Scholar 

  • Ehrlich BE, Kaftan E, Bezprozvannaya S, Bezprozvanny I (1994) The pharmacology of intracellular Ca2+-release channels. Trends Pharmacol Sci 15:145–149

    Article  CAS  PubMed  Google Scholar 

  • 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 17:1035–1043

    Article  CAS  PubMed  Google Scholar 

  • 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 559:761–776

    CAS  PubMed  Google Scholar 

  • 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 95:403–419

    Article  CAS  PubMed  Google Scholar 

  • 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 539:445–458

    Article  CAS  PubMed  Google Scholar 

  • 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 274:8375–8378

    Article  CAS  PubMed  Google Scholar 

  • 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 22:776–785

    Article  CAS  PubMed  Google Scholar 

  • 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 279:35741–35748

    Article  CAS  PubMed  Google Scholar 

  • Kayne LH, Lee DB (1993) Intestinal magnesium absorption. Miner Electrolyte Metab 19:210–217

    CAS  PubMed  Google Scholar 

  • Konrad M, Weber S (2003) Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249–260

    Article  PubMed  Google Scholar 

  • Kozak JA, Cahalan MD (2003) MIC channels are inhibited by internal divalent cations but not ATP. Biophys J 84:922–927

    Article  CAS  PubMed  Google Scholar 

  • Kozak JA, Kerschbaum HH, Cahalan MD (2002) Distinct properties of CRAC and MIC channels in RBL cells. J Gen Physiol 120:221–235

    PubMed  Google Scholar 

  • 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 69:1786–1791

    Article  CAS  PubMed  Google Scholar 

  • Luft JH (1971) Ruthenium red and violet. II. Fine structural localization in animal tissues. Anat Rec 171:369–415

    Article  CAS  PubMed  Google Scholar 

  • 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) 122:498–505

    CAS  PubMed  Google Scholar 

  • Meyer P, Boettger MB (2001) Familial hypomagnesaemia with secondary hypocalcaemia: a new case that indicates autosomal recessive inheritance. J Inherit Metab Dis 24:875–876

    Article  CAS  PubMed  Google Scholar 

  • 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 411:590–595

    Article  CAS  PubMed  Google Scholar 

  • 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 15:549–557

    Article  CAS  PubMed  Google Scholar 

  • 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 17:617–626

    Article  CAS  PubMed  Google Scholar 

  • 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 134:453–462

    Article  CAS  PubMed  Google Scholar 

  • 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 278:30813–30820

    Article  CAS  PubMed  Google Scholar 

  • Nilius B, Talavera K, Owsianik G, Prenen J, Droogmans G, Voets T (2005a) Gating of TRP channels: a voltage connection? J Physiol 567:35–44

    Article  CAS  PubMed  Google Scholar 

  • Nilius B, Voets T, Peters J (2005b) TRP channels in disease. Sci STKE 2005:eg7

    Google Scholar 

  • Paunier L, Radde IC, Kooh SW, Conen PE, Fraser D (1968) Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 41:385–402

    CAS  PubMed  Google Scholar 

  • 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 274:22739–22746

    Article  CAS  PubMed  Google Scholar 

  • Perretti M, Solito E (2004) Annexin 1 and neutrophil apoptosis. Biochem Soc Trans 32:507–510

    Article  CAS  PubMed  Google Scholar 

  • Prakriya M, Lewis RS (2002) Separation and characterization of currents through store-operated CRAC channels and Mg2+-inhibited cation (MIC) channels. J Gen Physiol 119:487–507

    Article  CAS  PubMed  Google Scholar 

  • Pronicka E, Gruszczynska B (1991) Familial hypomagnesaemia with secondary hypocalcaemia-autosomal or X-linked inheritance? J Inherit Metab Dis 14:397–399

    Article  CAS  PubMed  Google Scholar 

  • 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) 35:321–332

    CAS  Google Scholar 

  • Runnels LW, Yue L, Clapham DE (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291:1043–1047

    Article  CAS  PubMed  Google Scholar 

  • Runnels LW, Yue L, Clapham DE (2002) The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat Cell Biol 4:329–336

    CAS  PubMed  Google Scholar 

  • 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 279:3708–3716

    Article  CAS  PubMed  Google Scholar 

  • 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 31:166–170

    Article  CAS  PubMed  Google Scholar 

  • 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 114:191–200

    Article  CAS  PubMed  Google Scholar 

  • Schweigel M, Martens H (2000) Magnesium transport in the gastrointestinal tract. Front Biosci 5:D666–D677

    CAS  PubMed  Google Scholar 

  • Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645–655

    Article  PubMed  Google Scholar 

  • 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 438:1022–1025

    Article  CAS  PubMed  Google Scholar 

  • Visudhiphan P, Visudtibhan A, Chiemchanya S, Khongkhatithum C (2005) Neonatal seizures and familial hypomagnesemia with secondary hypocalcemia. Pediatr Neurol 33:202–205

    Article  PubMed  Google Scholar 

  • 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 277:33704–33710

    Article  CAS  PubMed  Google Scholar 

  • 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 279:19–25

    Article  CAS  PubMed  Google Scholar 

  • 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 6:1491–1497

    Article  CAS  PubMed  Google Scholar 

  • 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 31:171–174

    Article  CAS  PubMed  Google Scholar 

  • 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 290:998–1005

    CAS  PubMed  Google Scholar 

  • 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 145:405–414

    Article  CAS  PubMed  Google Scholar 

  • 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 7:1047–1057

    Article  CAS  PubMed  Google Scholar 

  • 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 4:153–164

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Bödding, M. (2007). TRPM6: A Janus-Like Protein. In: Flockerzi, V., Nilius, B. (eds) Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology, vol 179. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-34891-7_18

Download citation

Publish with us

Policies and ethics