Flavaglines Stimulate Transient Receptor Potential Melastatin Type 6 (TRPM6) Channel Activity

PLoS One. 2015 Mar 16;10(3):e0119028. doi: 10.1371/journal.pone.0119028. eCollection 2015.


Magnesium (Mg2+) is essential for enzymatic activity, brain function and muscle contraction. Blood Mg2+ concentrations are tightly regulated between 0.7 and 1.1 mM by Mg2+ (re)absorption in kidney and intestine. The apical entry of Mg2+ in (re)absorbing epithelial cells is mediated by the transient receptor potential melastatin type 6 (TRPM6) ion channel. Here, flavaglines are described as a novel class of stimulatory compounds for TRPM6 activity. Flavaglines are a group of natural and synthetic compounds that target the ubiquitously expressed prohibitins and thereby affect cellular signaling. By whole-cell patch clamp analyses, it was demonstrated that nanomolar concentrations of flavaglines increases TRPM6 activity by ∼2 fold. The stimulatory effects were dependent on the presence of the alpha-kinase domain of TRPM6, but did not require its phosphotransferase activity. Interestingly, it was observed that two natural occurring TRPM6 mutants with impaired insulin-sensitivity, TRPM6-p.Val1393Ile and TRPM6-p.Lys1584Glu, are not sensitive to flavagline stimulation. In conclusion, we have identified flavaglines as potent activators of TRPM6 activity. Our results suggest that flavaglines stimulate TRPM6 via the insulin receptor signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzofurans / pharmacology*
  • Binding Sites
  • HEK293 Cells
  • Humans
  • Magnesium / metabolism
  • Mutation
  • Prohibitins
  • Protein Structure, Tertiary
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • TRPM Cation Channels / chemistry*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*


  • Benzofurans
  • Prohibitins
  • Repressor Proteins
  • TRPM Cation Channels
  • TRPM6 protein, human
  • Magnesium

Grants and funding

This work was supported by grants from the Netherlands Organization for Scientific Research (ZonMW 9120.8026, NWO Vici 016.130.668) and the EURenOmics project from the European Union seventh framework programme (FP7/2007-2013, agreement no. 305608). The authors also thank the Association Nationale Recherche Technologie (ANRT) and the Association d’Aide à la Recherche et à l’Enseignement en Cancérologie (AAREC Filia Research) for fellowships to C. Basmadjian and Q. Zhao. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.