4.7 Article

TRPM7 is regulated by halides through its kinase domain

Journal

CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 70, Issue 15, Pages 2757-2771

Publisher

SPRINGER BASEL AG
DOI: 10.1007/s00018-013-1284-6

Keywords

TRPM7-inhibitor; Chloride; Iodide; Cell proliferation; Breast cancer

Funding

  1. National Institute for General Medical Science at the National Institutes of Health [P01GM078195]

Ask authors/readers for more resources

Transient receptor potential melastatin 7 (TRPM7) is a divalent-selective cation channel fused to an atypical alpha-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 (Mg2+), 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 Mg2+ ([Mg2+](i)) and this is facilitated through the ATP-binding site of the channel's kinase domain. The synergistic block of TRPM7 by chloride and Mg2+ 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 [Mg2+](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

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available