Article ; Online: Activation of TRPM7 channels by small molecules under physiological conditions.
Pflugers Archiv : European journal of physiology
2014 Volume 466, Issue 12, Page(s) 2177–2189
Abstract: ... small-molecule activators of TRPM7 channels, thus providing new experimental tools to study TRPM7 ... action was selective among the TRP channels tested. Naltriben activates TRPM7 currents without prior ... in the pore, TRP, and kinase domains indicate that the site of TRPM7 activation by this small-molecule ligand ...
| 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 Mg(2+) 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 Mg(2+) 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. |
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| MeSH term(s) | Action Potentials ; Animals ; HEK293 Cells ; Humans ; Magnesium/metabolism ; Mice ; Naltrexone/analogs & derivatives ; Naltrexone/pharmacology ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; TRPM Cation Channels/agonists ; TRPM Cation Channels/metabolism | |||||
| Chemical Substances | Phosphatidylinositol 4,5-Diphosphate ; Small Molecule Libraries ; TRPM Cation Channels ; naltrindole benzofuran (111555-58-9) ; Naltrexone (5S6W795CQM) ; Trpm7 protein, mouse (EC 2.7.1.-) ; Magnesium (I38ZP9992A) | |||||
| Language | English | |||||
| Publishing date | 2014-03-15 | |||||
| Publishing country | Germany | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 6380-0 | |||||
| ISSN | 1432-2013 ; 0031-6768 | |||||
| ISSN (online) | 1432-2013 | |||||
| ISSN | 0031-6768 | |||||
| DOI | 10.1007/s00424-014-1488-0 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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