Natural and synthetic modulators of SK (K(ca) 2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7.
|
Natural and synthetic modulators of SK (K(ca) 2) potassium channels inhibit magnesium-dependent activity of the kinase-coupled cation channel TRPM7.
|
Authors:
Address: Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Munich, Germany Institute of Pharmacology, University of Marburg, Marburg, Germany.
Journal:
Publication:
BACKGROUND and PURPOSE Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α-type protein kinase domain. TRPM7 is essential for proliferation and cell growth. Up-regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. the goal of this work was to identify non-toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells. EXPERIMENTAL APPROACH We developed an aequorin bioluminescence-based assay of TRPM7 channel activity and performed a hypothesis-driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments. KEY RESULTS TRPM7 currents were inhibited by modulators of small conductance Ca(2+) -activated K(+) channels (K(Ca) 2.1-2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC(50) 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg(2+) -dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7-like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes. CONCLUSIONS AND IMPLICATIONS This study reveals a tight overlap in the pharmacological profiles of TRPM7 and K(Ca) 2.1-2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well-suited to study functional features and cellular roles of endogenous TRPM7.
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
TraveldoctorOnline 2001 • Disclaimer • webmaster
The contents within traveldoctoronline are presented only for informational purposes and cannot substitute for professional health care or any other medical treatment.All users of this website with health problems should be oblige always to consult their medical doctor before starting any treatment.
