title: Flavaglines Stimulate Transient Receptor Potential Melastatin Type 6 (TRPM6) Channel Activity.
abstract: 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.
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maxime G
authors.initials: MG
authors.lastname: Blanchard
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jeroen H F
authors.initials: JH
authors.lastname: de Baaij
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sjoerd A J
authors.initials: SA
authors.lastname: Verkaart
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anke L
authors.initials: AL
authors.lastname: Lameris
authors.affiliation: Laboratory of Therapeutic Innovation (UMR7200), CNRS-University of Strasbourg, Faculty of Pharmacy, Illkirch, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Basmadjian
authors.affiliation: Laboratory of Therapeutic Innovation (UMR7200), CNRS-University of Strasbourg, Faculty of Pharmacy, Illkirch, France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Laboratory of Therapeutic Innovation (UMR7200), CNRS-University of Strasbourg, Faculty of Pharmacy, Illkirch, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
authors.affiliation: Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
mesh_terms: D001572:Benzofurans / Q000494:pharmacology*; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D009154:Mutation; D000091402:Prohibitins; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D000091402:Prohibitins; D012097:Repressor Proteins; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D008274:Magnesium