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¹ Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at the University of Hawaii, Honolulu, HI 96813
² Pacific Biomedical Research Center, University of Hawaii, Honolulu, HI 96822
³ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
⁴ Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, WA 98195

Address correspondence to Andrea Fleig, Center for Biomedical Research, The Queen's Medical Center University, Tower 8, 1301 Punchbowl Street, Honolulu, HI 96813. Fax: (808) 537-7899; E-mail: afleig{at}hawaii.edu

Trace metal ions such as Zn²⁺, Fe²⁺, Cu²⁺, Mn²⁺, and Co²⁺ are required cofactors for many essential cellular enzymes, yet little is known about the mechanisms through which they enter into cells. We have shown previously that the widely expressed ion channel TRPM7 (LTRPC7, ChaK1, TRP-PLIK) functions as a Ca²⁺- and Mg²⁺-permeable cation channel, whose activity is regulated by intracellular Mg²⁺ and Mg²⁺·ATP and have designated native TRPM7-mediated currents as magnesium-nucleotide–regulated metal ion currents (MagNuM). Here we report that heterologously overexpressed TRPM7 in HEK-293 cells conducts a range of essential and toxic divalent metal ions with strong preference for Zn²⁺ and Ni²⁺, which both permeate TRPM7 up to four times better than Ca²⁺. Similarly, native MagNuM currents are also able to support Zn²⁺ entry. Furthermore, TRPM7 allows other essential metals such as Mn²⁺ and Co²⁺ to permeate, and permits significant entry of nonphysiologic or toxic metals such as Cd²⁺, Ba²⁺, and Sr²⁺. Equimolar replacement studies substituting 10 mM Ca²⁺ with the respective divalent ions reveal a unique permeation profile for TRPM7 with a permeability sequence of Zn²⁺ Ni²⁺ >> Ba²⁺ > Co²⁺ > Mg²⁺ Mn²⁺ Sr²⁺ Cd²⁺ Ca²⁺, while trivalent ions such as La³⁺ and Gd³⁺ are not measurably permeable. With the exception of Mg²⁺, which exerts strong negative feedback from the intracellular side of the pore, this sequence is faithfully maintained when isotonic solutions of these divalent cations are used. Fura-2 quenching experiments with Mn²⁺, Co²⁺, or Ni²⁺ suggest that these can be transported by TRPM7 in the presence of physiological levels of Ca²⁺ and Mg²⁺, suggesting that TRPM7 represents a novel ion-channel mechanism for cellular metal ion entry into vertebrate cells.

Key Words: zinc • magnesium • nucleotide • trp channel • cation channel

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