Journal
CELL CALCIUM
Volume 41, Issue 6, Pages 513-523Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2006.10.003
Keywords
magnesium; HSH; ion channels; selectivity filter
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TRPM6 and its closest relative TRPM7 are members of the Transient Receptor Potential Melastatin (TRPM) subfamily of cation channels and are known to be Mg2+ permeable. By aligning the sequence of the putative TRPM6 pore with the pore sequences of the other subfamily members, we located in the loop between the fifth and the sixth transmembrame domain, a stretch of amino acids residues, (1028)GEIDVC(1033), as the potential selectivity filter. Two negatively charged residues, E-1024 (conserved in TRPM6, TRPM7, TRPM1 and TRPM3) and D-1031 (conserved along the entire TRPM subfamily), were identified as important determinants of cation permeation through TRPM6, because neutralization of both residues into an alanine resulted in non-functional channels. Neutralization of E-1029 (conserved in TRPM6, TRPM7, TRPM4 and TRPM5) resulted in channels with increased conductance for Ba2+ and Zn2+, decreased ruthenium red sensitivity and larger pore diameter compared to wild-type TRPM6. Changing the residue 110311 into methionine, resulted in channels with lower conductance for Ni2+, decreased sensitivity to ruthenium red block and reduced pore diameter. Thus, these data demonstrate that amino acid residues E-1024, I-1030 and D-1031 are important for channel function and that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties. (C) 2006 Elsevier Ltd. All rights reserved.
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