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J. Biol. Chem., Vol. 283, Issue 22, 15097-15103, May 30, 2008

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Proton Conductivity through the Human TRPM7 Channel and Its Molecular Determinants^*

From the Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan

TRPM7 is a divalent cation-permeable channel that is ubiquitously expressed. Recently, mouse TRPM7 has been shown to be sensitive to, and even permeable to, protons when heterologously expressed. Here we have demonstrated that human TRPM7 expressed either heterologously or endogenously also exhibits proton conductivity. The gene silencing of TRPM7 by small interfering RNA suppressed H⁺ currents in human cervical epithelial HeLa cells. In HEK293T cells transfected with human TRPM7, the inward proton conductance was suppressed by extracellular Mg²⁺ or Ca²⁺ with IC₅₀ values of 0.5 and 1.9 mM, respectively. Anomalous mole fraction behavior of H⁺ currents in the presence of Mg²⁺ or Ca²⁺ indicated that these divalent cations compete with protons for binding sites. Systematic mutation of negatively charged amino acid residues within the putative pore-forming region of human TRPM7 into the neutral amino acid alanine was tested. E1047A resulted in non-functional channels, and D1054A abolished proton conductance, whereas E1052A and D1059A only partially reduced proton conductivity. Thus, it is concluded that Asp-1054 is an essential determinant of the proton conductivity, whereas Glu-1047 might be required for channel formation, and the remaining negatively charged amino acids in the pore region (Glu-1052 and Asp-1059) may play a facilitating role in the proton conductivity of human TRPM7. It is suggested that proton conductivity of endogenous human TRPM7 plays a role in physiologically/pathologically acidic situations.

Received for publication, November 12, 2007 , and in revised form, March 5, 2008.

^* This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan and from the Japan Society for the Promotion of Science and by the Foundation for Promotion of Material Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1 and 2.

¹ Present address: Dept. of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Kyoto 615-8510, Japan.

² To whom correspondence should be addressed. Tel.: 81-564-55-7731; Fax: 81-564-55-7735; E-mail: okada{at}nips.ac.jp.

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