title: TRPM7 is regulated by halides through its kinase domain.
abstract: Transient receptor potential melastatin 7 (TRPM7) is a divalent-selective cation channel fused to an atypical α-kinase. TRPM7 is a key regulator of cell growth and proliferation, processes accompanied by mandatory cell volume changes. Osmolarity-induced cell volume alterations regulate TRPM7 through molecular crowding of solutes that affect channel activity, including magnesium (Mg(2+)), Mg-nucleotides and a further unidentified factor. Here, we assess whether chloride and related halides can act as negative feedback regulators of TRPM7. We find that chloride and bromide inhibit heterologously expressed TRPM7 in synergy with intracellular Mg(2+) ([Mg(2+)]i) and this is facilitated through the ATP-binding site of the channel's kinase domain. The synergistic block of TRPM7 by chloride and Mg(2+) is not reversed during divalent-free or acidic conditions, indicating a change in protein conformation that leads to channel inactivation. Iodide has the strongest inhibitory effect on TRPM7 at physiological [Mg(2+)]i. Iodide also inhibits endogenous TRPM7-like currents as assessed in MCF-7 breast cancer cells, where upregulation of SLC5A5 sodium-iodide symporter enhances iodide uptake and inhibits cell proliferation. These results indicate that chloride could be an important factor in modulating TRPM7 during osmotic stress and implicate TRPM7 as a possible molecular mechanism contributing to the anti-proliferative characteristics of intracellular iodide accumulation in cancer cells.
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI 96813, USA.
authors.forename: Haijie
authors.initials: H
authors.lastname: Yu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Annette
authors.initials: A
authors.lastname: Lis
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001965:Bromides / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism / Q000494:pharmacology*; D018076:DNA, Complementary / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007454:Iodides / Q000378:metabolism / Q000494:pharmacology*; D061986:MCF-7 Cells; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D027981:Symporters / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism* / Q000502:physiology; D000099209:Sodium-Iodide Symporters
chemical_list: D000255:Adenosine Triphosphate; D001965:Bromides; D002712:Chlorides; D018076:DNA, Complementary; D007454:Iodides; D017346:Protein Serine-Threonine Kinases; D027981:Symporters; D050053:TRPM Cation Channels; D000099209:Sodium-Iodide Symporters; C486583:TRPM7 protein, human