Skip to main content

Advertisement

SpringerLink
Log in

Activation of TRPM7 channels by small molecules under physiological conditions

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a cation channel covalently linked to a protein kinase domain. TRPM7 is ubiquitously expressed and regulates key cellular processes such as Mg2+ homeostasis, motility, and proliferation. TRPM7 is involved in anoxic neuronal death, cardiac fibrosis, and tumor growth. The goal of this work was to identify small molecule activators of the TRPM7 channel and investigate their mechanism of action. We used an aequorin bioluminescence-based assay to screen for activators of the TRPM7 channel. Valid candidates were further characterized using patch clamp electrophysiology. We identified 20 drug-like compounds with various structural backbones that can activate the TRPM7 channel. Among them, the δ opioid antagonist naltriben was studied in greater detail. Naltriben’s action was selective among the TRP channels tested. Naltriben activates TRPM7 currents without prior depletion of intracellular Mg2+ even under conditions of low PIP2. Moreover, naltriben interfered with the effect of the TRPM7 inhibitor NS8593. Finally, our experiments with TRPM7 variants carrying mutations in the pore, TRP, and kinase domains indicate that the site of TRPM7 activation by this small-molecule ligand is most likely located in or near the TRP domain. In conclusion, we identified the first organic small-molecule activators of TRPM7 channels, thus providing new experimental tools to study TRPM7 function in native cellular environments.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

TRPM7:

Melastatin-related TRP cation channel 7

PIP2 :

Phosphatidylinositol 4,5-bisphosphate

PLC:

Phospholipid lipase C

GPCRs:

G-protein-coupled receptors

References

  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(7):863–877

    Article  PubMed  CAS  Google Scholar 

  2. Abed E, Martineau C, Moreau R (2011) Role of melastatin transient receptor potential 7 channels in the osteoblastic differentiation of murine MC3T3 cells. Calcif Tissue Int 88(3):246–253. doi:10.1007/s00223-010-9455-z

    Article  PubMed  CAS  Google Scholar 

  3. Bates-Withers C, Sah R, Clapham DE (2011) TRPM7, the Mg(2+) inhibited channel and kinase. Adv Exp Med Biol 704:173–183. doi:10.1007/978-94-007-0265-3_9

    Article  PubMed  CAS  Google Scholar 

  4. Baubet V, Le Mouellic H, Campbell AK, Lucas-Meunier E, Fossier P, Brulet P (2000) Chimeric green fluorescent protein-aequorin as bioluminescent Ca2+ reporters at the single-cell level. Proc Natl Acad Sci U S A 97(13):7260–7265

    Google Scholar 

  5. Brauchi S, Krapivinsky G, Krapivinsky L, Clapham DE (2008) TRPM7 facilitates cholinergic vesicle fusion with the plasma membrane. Proc Natl Acad Sci U S A 105(24):8304–8308. doi:10.1073/pnas.0800881105

    Article  PubMed Central  PubMed  Google Scholar 

  6. Cao E, Liao M, Cheng Y, Julius D (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504(7478):113–118. doi:10.1038/nature12823

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. 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(6653):816–824. doi:10.1038/39807

    Article  PubMed  CAS  Google Scholar 

  8. Chen YF, Chen YT, Chiu WT, Shen MR (2013) Remodeling of calcium signaling in tumor progression. J Biomed Sci 20:23. doi:10.1186/1423-0127-20-23

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Chen JP, Luan Y, You CX, Chen XH, Luo RC, Li R (2010) TRPM7 regulates the migration of human nasopharyngeal carcinoma cell by mediating Ca(2+) influx. Cell Calcium 47(5):425–432. doi:10.1016/j.ceca.2010.03.003

    Article  PubMed  CAS  Google Scholar 

  10. Chen KH, Xu XH, Liu Y, Hu Y, Jin MW, Li GR (2013) TRPM7 channels regulate proliferation and adipogenesis in 3T3-L1 preadipocytes. J Cell Physiol 229(1):60–67. doi:10.1002/jcp.24417

    Google Scholar 

  11. Chubanov V, Mederos y Schnitzler M, Meissner M, Schafer S, Abstiens K, Hofmann T, Gudermann T (2012) Natural and synthetic modulators of SK (K(ca)2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7. Br J Pharmacol 166(4):1357–1376. doi:10.1111/j.1476-5381.2012.01855.x

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Chubanov V, Schlingmann KP, Waring J, Heinzinger J, Kaske S, Waldegger S, Mederos y Schnitzler M, Gudermann T (2007) Hypomagnesemia with secondary hypocalcemia due to a missense mutation in the putative pore-forming region of TRPM6. J Biol Chem 282(10):7656–7667. doi:10.1074/jbc.M611117200

    Article  PubMed  CAS  Google Scholar 

  13. 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(9):2894–2899. doi:10.1073/pnas.03052521010305252101

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Clark K, Langeslag M, van Leeuwen B, Ran L, Ryazanov AG, Figdor CG, Moolenaar WH, Jalink K, van Leeuwen FN (2006) TRPM7, a novel regulator of actomyosin contractility and cell adhesion. EMBO J 25(2):290–301. doi:10.1038/sj.emboj.7600931

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Clark K, Middelbeek J, Morrice NA, Figdor CG, Lasonder E, van Leeuwen FN (2008) Massive autophosphorylation of the Ser/Thr-rich domain controls protein kinase activity of TRPM6 and TRPM7. PLoS One 3(3):e1876. doi:10.1371/journal.pone.0001876

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Dai Q, Shrubsole MJ, Ness RM, Schlundt D, Cai Q, Smalley WE, Li M, Shyr Y, Zheng W (2007) The relation of magnesium and calcium intakes and a genetic polymorphism in the magnesium transporter to colorectal neoplasia risk. Am J Clin Nutr 86(3):743–751

    PubMed Central  PubMed  CAS  Google Scholar 

  17. Deason-Towne F, Perraud AL, Schmitz C (2012) Identification of Ser/Thr phosphorylation sites in the C2-domain of phospholipase C gamma2 (PLCgamma2) using TRPM7-kinase. Cell Signal 24(11):2070–2075. doi:10.1016/j.cellsig.2012.06.015

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Demeuse P, Penner R, Fleig A (2006) TRPM7 channel is regulated by magnesium nucleotides via its kinase domain. J Gen Physiol 127(4):421–434. doi:10.1085/jgp.200509410

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Desai BN, Krapivinsky G, Navarro B, Krapivinsky L, Carter BC, Febvay S, Delling M, Penumaka A, Ramsey IS, Manasian Y, Clapham DE (2012) Cleavage of TRPM7 releases the kinase domain from the ion channel and regulates its participation in Fas-induced apoptosis. Dev Cell 22(6):1149–1162. doi:10.1016/j.devcel.2012.04.006

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Dharmshaktu P, Tayal V, Kalra BS (2012) Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 52(1):6–17. doi:10.1177/0091270010394852

    Article  PubMed  CAS  Google Scholar 

  21. Dorovkov MV, Kostyukova AS, Ryazanov AG (2011) Phosphorylation of annexin A1 by TRPM7 kinase: a switch regulating the induction of an alpha-helix. Biochemistry 50(12):2187–2193. doi:10.1021/bi101963h

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D, Liang B, Yue L (2010) TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res 106(5):992–1003. doi:10.1161/CIRCRESAHA.109.206771

    Google Scholar 

  23. Elizondo MR, Arduini BL, Paulsen J, MacDonald EL, Sabel JL, Henion PD, Cornell RA, Parichy DM (2005) Defective skeletogenesis with kidney stone formation in dwarf zebrafish mutant for trpm7. Curr Biol 15(7):667–671. doi:10.1016/j.cub.2005.02.050

    Article  PubMed  CAS  Google Scholar 

  24. Gao H, Chen X, Du X, Guan B, Liu Y, Zhang H (2011) EGF enhances the migration of cancer cells by up-regulation of TRPM7. Cell Calcium 50(6):559–568. doi:10.1016/j.ceca.2011.09.003

    Article  PubMed  CAS  Google Scholar 

  25. Guilbert A, Gautier M, Dhennin-Duthille I, Haren N, Sevestre H, Ouadid-Ahidouch H (2009) Evidence that TRPM7 is required for breast cancer cell proliferation. Am J Physiol Cell Physiol 297(3):C493–C502. doi:10.1152/ajpcell.00624.2008

    Article  PubMed  CAS  Google Scholar 

  26. 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(4):403–419

    Google Scholar 

  27. Hara K, Kokubo Y, Ishiura H, Fukuda Y, Miyashita A, Kuwano R, Sasaki R, Goto J, Nishizawa M, Kuzuhara S, Tsuji S (2009) TRPM7 is not associated with amyotrophic lateral sclerosis-parkinsonism dementia complex in the Kii peninsula of Japan. Am J Med Genet B Neuropsychiatr Genet 153B(1):310–313. doi:10.1002/ajmg.b.30966

    Google Scholar 

  28. Hermosura MC, Nayakanti H, Dorovkov MV, Calderon FR, Ryazanov AG, Haymer DS, Garruto RM (2005) A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc Natl Acad Sci U S A 102(32):11510–11515. doi:10.1073/pnas.0505149102

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Jiang J, Li MH, Inoue K, Chu XP, Seeds J, Xiong ZG (2007) Transient receptor potential melastatin 7-like current in human head and neck carcinoma cells: role in cell proliferation. Cancer Res 67(22):10929–10938. doi:10.1158/0008-5472.CAN-07-1121

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Jiang J, Li M, Yue L (2005) Potentiation of TRPM7 inward currents by protons. J Gen Physiol 126(2):137–150. doi:10.1085/jgp.200409185

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Jin J, Desai BN, Navarro B, Donovan A, Andrews NC, Clapham DE (2008) Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322(5902):756–760. doi:10.1126/science.1163493

    Google Scholar 

  32. Jin J, Wu LJ, Jun J, Cheng X, Xu H, Andrews NC, Clapham DE (2011) The channel kinase, TRPM7, is required for early embryonic development. Proc Natl Acad Sci U S A 109(5):E225–E233. doi:10.1073/pnas.1120033109

    Article  PubMed Central  PubMed  Google Scholar 

  33. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427(6971):260–265. doi:10.1038/nature02282nature02282

    Article  PubMed  CAS  Google Scholar 

  34. Julius D (2013) TRP channels and pain. Annu Rev Cell Dev Biol 29:355–384. doi:10.1146/annurev-cellbio-101011-155833

    Article  PubMed  CAS  Google Scholar 

  35. Kim BJ, Park EJ, Lee JH, Jeon JH, Kim SJ, So I (2008) Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer. Cancer Sci 99(12):2502–2509. doi:10.1111/j.1349-7006.2008.00982.x

    Article  PubMed  CAS  Google Scholar 

  36. Kozak JA, Kerschbaum HH, Cahalan MD (2002) Distinct properties of CRAC and MIC channels in RBL cells. J Gen Physiol 120(2):221–235

    PubMed Central  PubMed  Google Scholar 

  37. Kozak JA, Matsushita M, Nairn AC, Cahalan MD (2005) Charge screening by internal pH and polyvalent cations as a mechanism for activation, inhibition, and rundown of TRPM7/MIC channels. J Gen Physiol 126(5):499–514. doi:10.1085/jgp.200509324

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Kuras Z, Yun YH, Chimote AA, Neumeier L, Conforti L (2012) KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells. PLoS One 7(8):e43859. doi:10.1371/journal.pone.0043859PONE-D-11-17226

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F, Drago F (2013) Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol 719(1–3):25–33. doi:10.1016/j.ejphar.2013.07.022

    Article  PubMed  CAS  Google Scholar 

  40. Mederos y Schnitzler M, Waring J, Gudermann T, Chubanov V (2008) Evolutionary determinants of divergent calcium selectivity of TRPM channels. FASEB J 22(5):1540–1551. doi:10.1096/fj.07-9694com

    Article  PubMed  CAS  Google Scholar 

  41. Meng X, Cai C, Wu J, Cai S, Ye C, Chen H, Yang Z, Zeng H, Shen Q, Zou F (2013) TRPM7 mediates breast cancer cell migration and invasion through the MAPK pathway. Cancer Lett 333(1):96–102. doi:10.1016/j.canlet.2013.01.031

    Article  PubMed  CAS  Google Scholar 

  42. Middelbeek J, Kuipers AJ, Henneman L, Visser D, Eidhof I, van Horssen R, Wieringa B, Canisius SV, Zwart W, Wessels LF, Sweep FC, Bult P, Span PN, van Leeuwen FN, Jalink K (2012) TRPM7 is required for breast tumor cell metastasis. Cancer Res 72(16):4250–4261. doi:10.1158/0008-5472.CAN-11-3863

    Article  PubMed  CAS  Google Scholar 

  43. Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A (2003) TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121(1):49–60

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Mubagwa K, Gwanyanya A, Zakharov S, Macianskiene R (2007) Regulation of cation channels in cardiac and smooth muscle cells by intracellular magnesium. Arch Biochem Biophys 458(1):73–89. doi:10.1016/j.abb.2006.10.014

    Article  PubMed  CAS  Google Scholar 

  45. 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(6837):590–595. doi:10.1038/3507909235079092

    Article  PubMed  CAS  Google Scholar 

  46. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87(1):165–217. doi:10.1152/physrev.00021.2006

    Article  PubMed  CAS  Google Scholar 

  47. Numata T, Shimizu T, Okada Y (2007) Direct mechano-stress sensitivity of TRPM7 channel. Cell Physiol Biochem 19(1–4):1–8. doi:10.1159/000099187

    Article  PubMed  CAS  Google Scholar 

  48. Oancea E, Wolfe JT, Clapham DE (2006) Functional TRPM7 channels accumulate at the plasma membrane in response to fluid flow. Circ Res 98(2):245–253. doi:10.1161/01.RES.0000200179.29375.cc

    Article  PubMed  CAS  Google Scholar 

  49. Paravicini TM, Chubanov V, Gudermann T (2012) TRPM7: a unique channel involved in magnesium homeostasis. Int J Biochem Cell Biol 44(8):1381–1384. doi:10.1016/j.biocel.2012.05.010

    Article  PubMed  CAS  Google Scholar 

  50. Patapoutian A, Tate S, Woolf CJ (2009) Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8(1):55–68. doi:10.1038/nrd2757

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108(5):705–715

    Article  PubMed  CAS  Google Scholar 

  52. Penner R, Fleig A (2007) The Mg(2+) and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol 179:313–328. doi:10.1007/978-3-540-34891-7_19

    Google Scholar 

  53. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM (2001) ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411(6837):595–599. doi:10.1038/3507910035079100

    Article  PubMed  CAS  Google Scholar 

  54. Perraud AL, Zhao X, Ryazanov AG, Schmitz C (2010) The channel-kinase TRPM7 regulates phosphorylation of the translational factor eEF2 via eEF2-k. Cell Signal 23(3):586–593. doi:10.1016/j.cellsig.2010.11.011

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Runnels LW (2010) TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions. Curr Pharm Biotechnol 12(1):42–53

    Article  Google Scholar 

  56. Runnels LW, Yue L, Clapham DE (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291(5506):1043–1047. doi:10.1126/science.10585191058519

    Article  PubMed  CAS  Google Scholar 

  57. Runnels LW, Yue L, Clapham DE (2002) The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat Cell Biol 4(5):329–336. doi:10.1038/ncb781ncb781

    PubMed  CAS  Google Scholar 

  58. Ryazanov AG, Pavur KS, Dorovkov MV (1999) Alpha-kinases: a new class of protein kinases with a novel catalytic domain. Curr Biol 9(2):R43–R45

    Article  PubMed  CAS  Google Scholar 

  59. Ryazanova LV, Rondon LJ, Zierler S, Hu Z, Galli J, Yamaguchi TP, Mazur A, Fleig A, Ryazanov AG (2010) TRPM7 is essential for Mg(2+) homeostasis in mammals. Nat Commun 1:109. doi:10.1038/ncomms1108

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. Rybarczyk P, Gautier M, Hague F, Dhennin-Duthille I, Chatelain D, Kerr-Conte J, Pattou F, Regimbeau JM, Sevestre H, Ouadid-Ahidouch H (2012) Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration. Int J Cancer 131(6):E851–E861. doi:10.1002/ijc.27487

    Article  PubMed  CAS  Google Scholar 

  61. Sah R, Mesirca P, Mason X, Gibson W, Bates-Withers C, Van den Boogert M, Chaudhuri D, Pu WT, Mangoni ME, Clapham DE (2013) Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization. Circulation 128(2):101–114. doi:10.1161/CIRCULATIONAHA.112.000768

    Article  PubMed  CAS  Google Scholar 

  62. Sah R, Mesirca P, Van den Boogert M, Rosen J, Mably J, Mangoni ME, Clapham DE (2013) Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity. Proc Natl Acad Sci U S A 110(32):E3037–E3046. doi:10.1073/pnas.1311865110

    Article  PubMed Central  PubMed  Google Scholar 

  63. Sahni J, Scharenberg AM (2008) TRPM7 ion channels are required for sustained phosphoinositide 3-kinase signaling in lymphocytes. Cell Metab 8(1):84–93. doi:10.1016/j.cmet.2008.06.002

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. 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(2):191–200

    Article  PubMed  CAS  Google Scholar 

  65. Siddiqui TA, Lively S, Vincent C, Schlichter LC (2012) Regulation of podosome formation, microglial migration and invasion by Ca(2+)-signaling molecules expressed in podosomes. J Neuroinflammation 9:250. doi:10.1186/1742-2094-9-250

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Sofuoglu M, Portoghese PS, Takemori AE (1991) Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta opioid receptor subtypes. J Pharmacol Exp Ther 257(2):676–680

    PubMed  CAS  Google Scholar 

  67. Su LT, Agapito MA, Li M, Simonson WT, Huttenlocher A, Habas R, Yue L, Runnels LW (2006) TRPM7 regulates cell adhesion by controlling the calcium-dependent protease calpain. J Biol Chem 281(16):11260–11270. doi:10.1074/jbc.M512885200

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Su LT, Liu W, Chen HC, Gonzalez-Pagan O, Habas R, Runnels LW (2011) TRPM7 regulates polarized cell movements. Biochem J 434(3):513–521. doi:10.1042/BJ20101678

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Suh BC, Hille B (2008) PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys 37:175–195. doi:10.1146/annurev.biophys.37.032807.125859

    Google Scholar 

  70. Takemori AE, Sultana M, Nagase H, Portoghese PS (1992) Agonist and antagonist activities of ligands derived from naltrexone and oxymorphone. Life Sci 50(20):1491–1495

    Article  PubMed  CAS  Google Scholar 

  71. Touyz RM (2008) Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension. Am J Physiol Heart Circ Physiol 294(3):H1103–H1118. doi:10.1152/ajpheart.00903.2007

    Article  PubMed  Google Scholar 

  72. Tramer MR, von Elm E, Loubeyre P, Hauser C (2006) Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review. BMJ 333(7570):675. doi:10.1136/bmj.38905.634132.AE

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Tseveleki V, Rubio R, Vamvakas SS, White J, Taoufik E, Petit E, Quackenbush J, Probert L (2010) Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes. Genomics 96(2):82–91. doi:10.1016/j.ygeno.2010.04.004

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Voets T, Owsianik G, Janssens A, Talavera K, Nilius B (2007) TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol 3(3):174–182. doi:10.1038/nchembio862

    Article  PubMed  CAS  Google Scholar 

  75. Vriens J, Held K, Janssens A, Toth BI, Kerselaers S, Nilius B, Vennekens R, Voets T (2014) Opening of an alternative ion permeation pathway in a nociceptor TRP channel. Nat Chem Biol. doi:10.1038/nchembio.1428

    PubMed  Google Scholar 

  76. Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, Dufer M, Lis A, Flockerzi V, Philipp SE, Oberwinkler J (2008) Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells. Nat Cell Biol 10(12):1421–1430. doi:10.1038/ncb1801

    Article  PubMed  CAS  Google Scholar 

  77. Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, Vriens J, Cairns W, Wissenbach U, Prenen J, Flockerzi V, Droogmans G, Benham CD, Nilius B (2002) Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem 277(16):13569–13577. doi:10.1074/jbc.M200062200M200062200

    Article  PubMed  CAS  Google Scholar 

  78. Wei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H (2009) Calcium flickers steer cell migration. Nature 457(7231):901–905. doi:10.1038/nature07577

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Wenthur CJ, Lindsley CW (2013) Classics in chemical neuroscience: clozapine. ACS Chem Neurosci 4(7):1018–1025. doi:10.1021/cn400121z

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. 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(5):1047–1057

    Article  PubMed  CAS  Google Scholar 

  81. Zhang Z, Wang M, Fan XH, Chen JH, Guan YY, Tang YB (2012) Upregulation of TRPM7 channels by angiotensin II triggers phenotypic switching of vascular smooth muscle cells of ascending aorta. Circ Res 111(9):1137–1146. doi:10.1161/CIRCRESAHA.112.273755

    Article  PubMed  CAS  Google Scholar 

  82. Zierler S, Yao G, Zhang Z, Kuo WC, Porzgen P, Penner R, Horgen FD, Fleig A (2011) Waixenicin A inhibits cell proliferation through magnesium-dependent block of transient receptor potential melastatin 7 (TRPM7) channels. J Biol Chem 286(45):39328–39335. doi:10.1074/jbc.M111.264341

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG), including an Emmy-Noether-Fellowship to T.H. (DFG-Ho-3869). S.S. was supported by the Förderprogramm für Forschung und Lehre Fellowship (FöFoLe) of the LMU, Munich. We thank Renate Heilmair for excellent technical assistance and Moritz Meißner and Anna Erbacher for their help with the primary screen.

Conflict of interest

None

Author information

Authors and Affiliations

  1. Philipps-Universität Marburg, Klinik für Innere Medizin/Nephrologie, Baldingerstraße 1, 35043, Marburg, Germany

    T. Hofmann

  2. Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany

    S. Schäfer, M. Linseisen, L. Sytik, T. Gudermann & V. Chubanov

Authors
  1. T. Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Schäfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Linseisen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Sytik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Gudermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. Chubanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to T. Hofmann or V. Chubanov.

Additional information

T. Hofmann and S. Schäfer contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hofmann, T., Schäfer, S., Linseisen, M. et al. Activation of TRPM7 channels by small molecules under physiological conditions. Pflugers Arch - Eur J Physiol 466, 2177–2189 (2014). https://doi.org/10.1007/s00424-014-1488-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1488-0

Keywords

Search

Navigation