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. 2012 Jun;166(4):1357-76. doi: 10.1111/j.1476-5381.2012.01855.x.


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 Ca²⁺ -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 (IC₅₀ 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg²⁺ -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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Naphthylamine / adverse effects
  • 1-Naphthylamine / analogs & derivatives
  • 1-Naphthylamine / pharmacology
  • Animals
  • Calcium Signaling / drug effects
  • Cell Movement / drug effects
  • Cells, Cultured
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Magnesium / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Transport Modulators / adverse effects
  • Membrane Transport Modulators / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Podocytes / cytology
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Potassium Channel Blockers / adverse effects
  • Potassium Channel Blockers / pharmacology*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Serine-Threonine Kinases
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors*
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism


  • (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine
  • Membrane Transport Modulators
  • Potassium Channel Blockers
  • Protein Isoforms
  • Recombinant Proteins
  • Small-Conductance Calcium-Activated Potassium Channels
  • TRPM Cation Channels
  • 1-Naphthylamine
  • Trpm7 protein, mouse
  • Protein Serine-Threonine Kinases
  • TRPM7 protein, human
  • Magnesium