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Biophysical Journal 84:922-927 (2003)
© 2003 The Biophysical Society

MIC Channels Are Inhibited by Internal Divalent Cations but Not ATP

J. Ashot Kozak and Michael D. Cahalan

Department of Physiology and Biophysics, University of California, Irvine, California 92697

Correspondence: Address reprint requests to Michael D. Cahalan, Dept. of Physiology and Biophysics, University of California, Irvine, CA 92697-4561. Tel.: 949-824-7776; Fax: 949-824-3143; E-mail: mcahalan{at}uci.edu.

TRPM7 channels are nonselective cation channels that possess a functional {alpha}-kinase domain. It has been proposed that heterologously expressed TRPM7 channels are activated (Runnels et al., 2001) or inhibited (Nadler et al., 2001) by dialyzing the cell with millimolar levels of ATP. The endogenous correlate of TRPM7 has been identified in T-lymphocytes and RBL (rat basophilic leukemia) cells and named MagNuM (for Mg2+-nucleotide-inhibited metal) or MIC (for Mg2+-inhibited cation). Here, we report that internal Mg2+ rather than MgATP inhibits this current. Cytoplasmic MgATP, supplied by dialysis at millimolar concentrations, effectively inhibits only when a weak Mg2+ chelator is present in the pipette solution. Thus, MgATP acts as a source of Mg2+ rather than a source of ATP. Using an externally accessible site within the pore of the MIC channel itself as a bioassay, we show that equimolar MgCl2 and MgATP solutions contain similar amounts of free Mg2+, explaining the fact that numeric values of Mg2+ and MgATP concentrations necessary for complete inhibition are the same. Furthermore, we demonstrate that Mg2+ is not unique in its inhibitory action, as Ba2+, Sr2+, Zn2+, and Mn2+ can substitute for Mg2+, causing complete inhibition. We conclude that MIC current inhibition occurs simply by divalent cations.




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