CHANNELS A Magnesium Feedback Loop to Homeostasis

Schmitz et al. obtained evidence that implicated TRPM7, a member of the TRPM family of cation channels that contains both ion channels and protein kinase domains, in the regulation of magnesium (Mg²⁺) uptake and homeostasis in eukaryotic cells. Mg²⁺ plays a critical role in regulating the function of various enzymes, receptors, and channels; the factors governing intracellular Mg²⁺ concentration [Mg²⁺]_i, however, remain poorly understood. The authors varied [Mg²⁺] over a physiologically relevant range and found that, as [Mg²⁺] was increased, in vitro autophosphorylation of TRPM7 was progressively enhanced, whereas ion currents (measured with whole-cell patch-clamp analysis of HEK293 cells transfected with human TRPM7) were progressively inhibited. Point mutations in the kinase domain that diminished its activity decreased TRPM7's sensitivity to Mg²⁺ inhibition of ionic current, whereas deletion of the entire kinase domain enhanced the sensitivity to Mg²⁺ inhibition. As previously reported, TRPM7 knockout led to the growth arrest and the death of cultured cells; this was associated with reduced [Mg²⁺]_i and could be reversed by increasing extracellular [Mg²⁺]. Expression of TRPM7 mutants in TRPM7-deficient cells indicated that the ability to maintain [Mg²⁺]_i and to support normal cell growth depended on TRPM7 sensitivity to suppression by Mg (so that the mutant lacking a kinase domain could only partially compensate for TRMP7 deficiency). These data suggest that TRPM7 may play a critical role in regulating [Mg²⁺]_i through Mg²⁺-dependent regulation of channel opening, thereby regulating Mg²⁺ influx.

C. Schmitz, A.-L. Perraud, C. O. Johnson, K. Inabe, M. K. Smith, R. Penner, T. Kurosaki, A. Fleig, A. M. Scharenberg, Regulation of vertebrate cellular Mg²⁺ homeostasis by TRPM. Cell 114, 191-200 (2003). [Online Journal]