title: Methionine sulfoxide reductase B1 (MsrB1) recovers TRPM6 channel activity during oxidative stress.
abstract: Mg(2+) is an essential ion for many cellular processes, including protein synthesis, nucleic acid stability, and numerous enzymatic reactions. Mg(2+) homeostasis in mammals depends on the equilibrium between intestinal absorption, renal excretion, and exchange with bone. The transient receptor potential melastatin type 6 (TRPM6) is an epithelial Mg(2+) channel, which is abundantly expressed in the luminal membrane of the renal and intestinal cells. It functions as the gatekeeper of transepithelial Mg(2+) transport. Remarkably, TRPM6 combines a Mg(2+)-permeable channel with an alpha-kinase domain. Here, by the Ras recruitment system, we identified methionine sulfoxide reductase B1 (MsrB1) as an interacting protein of the TRPM6 alpha-kinase domain. Importantly, MsrB1 and TRPM6 are both present in the renal Mg(2+)-transporting distal convoluted tubules. MsrB1 has no effect on TRPM6 channel activity in the normoxic conditions. However, hydrogen peroxide (H(2)O(2)) decreased TRPM6 channel activity. Co-expression of MsrB1 with TRPM6 attenuated the inhibitory effect of H(2)O(2) (TRPM6, 67 +/- 5% of control; TRPM6 + MsrB1, 81 +/- 5% of control). Cell surface biotinylation assays showed that H(2)O(2) treatment does not affect the expression of TRPM6 at the plasma membrane. Next, mutation of Met(1755) to Ala in TRPM6 reduced the inhibitory effect of H(2)O(2) on TRPM6 channel activity (TRPM6 M1755A: 84 +/- 10% of control), thereby mimicking the action of MsrB1. Thus, these data suggest that MsrB1 recovers TRPM6 channel activity by reducing the oxidation of Met(1755) and could, thereby, function as a modulator of TRPM6 during oxidative stress.
authors.affiliation: Department of Physiology, Radboud University Nijmegen Medical Centre, HB Nijmegen, The Netherlands.
authors.forename: Gang
authors.initials: G
authors.lastname: Cao
authors.forename: Kyu Pil
authors.initials: KP
authors.lastname: Lee
authors.forename: Jenny
authors.initials: J
authors.lastname: van der Wijst
authors.forename: Mark
authors.initials: M
authors.lastname: de Graaf
authors.forename: Annemiete
authors.initials: A
authors.lastname: van der Kemp
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000502:physiology*; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C530168:Trpm6 protein, mouse; D008715:Methionine; D006861:Hydrogen Peroxide; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D008274:Magnesium