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: Haijie Yu, Zheng Zhang, Annette Lis, Reinhold Penner, Andrea Fleig
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 70 Issue 15 Pg. 2757-71 (Aug 2013) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 23471296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Bromides
• Chlorides
• DNA, Complementary
• Iodides
• Symporters
• TRPM Cation Channels
• sodium-iodide symporter
• Adenosine Triphosphate
• Protein Serine-Threonine Kinases
• TRPM7 protein, human

Topics

• Adenosine Triphosphate (metabolism)
• Bromides (metabolism, pharmacology)
• Cell Proliferation (drug effects)
• Chlorides (metabolism, pharmacology)
• DNA, Complementary (biosynthesis)
• Dose-Response Relationship, Drug
• Feedback, Physiological (physiology)
• Gene Expression Regulation (physiology)
• HEK293 Cells
• Humans
• Hydrogen-Ion Concentration
• Inhibitory Concentration 50
• Iodides (metabolism, pharmacology)
• MCF-7 Cells
• Patch-Clamp Techniques
• Protein Serine-Threonine Kinases
• Protein Structure, Tertiary (physiology)
• Real-Time Polymerase Chain Reaction
• Symporters (metabolism)
• TRPM Cation Channels (metabolism, physiology)