Activation of TRPM7 channels by small molecules under physiological conditions

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