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  1. Article: Molecular determinants of permeation through the cation channel TRPM6.

    Topala, Catalin N / Groenestege, Wouter Tiel / Thébault, Stéphanie / van den Berg, Dennis / Nilius, Bernd / Hoenderop, Joost G / Bindels, René J

    Cell calcium

    2007  Volume 41, Issue 6, Page(s) 513–523

    Abstract: ... of cation permeation through TRPM6, because neutralization of both residues into an alanine resulted in non ... TRPM) subfamily of cation channels and are known to be Mg2+ permeable. By aligning the sequence ... that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties. ...

    Abstract 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 transmembrane domain, a stretch of amino acids residues, 1028GEIDVC1033, as the potential selectivity filter. Two negatively charged residues, E1024 (conserved in TRPM6, TRPM7, TRPM1 and TRPM3) and D1031 (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 E1029 (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 I1030 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 E1024, I1030 and D1031 are important for channel function and that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties.
    MeSH term(s) Amino Acid Sequence ; Cations/metabolism ; Cell Line ; Humans ; Ion Transport ; Magnesium/metabolism ; Molecular Sequence Data ; Mutation ; Patch-Clamp Techniques ; Ruthenium Red/pharmacology ; Sequence Alignment ; Sodium/metabolism ; TRPM Cation Channels/chemistry ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism ; Transfection
    Chemical Substances Cations ; TRPM Cation Channels ; TRPM6 protein, human ; Ruthenium Red (11103-72-3) ; Sodium (9NEZ333N27) ; Magnesium (I38ZP9992A)
    Language English
    Publishing date 2007-06
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 757687-0
    ISSN 1532-1991 ; 0143-4160
    ISSN (online) 1532-1991
    ISSN 0143-4160
    DOI 10.1016/j.ceca.2006.10.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1596: Show issues Location:
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  2. Article: Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7.

    Li, Mingjiang / Du, Jianyang / Jiang, Jianmin / Ratzan, William / Su, Li-Ting / Runnels, Loren W / Yue, Lixia

    The Journal of biological chemistry

    2007  Volume 282, Issue 35, Page(s) 25817–25830

    Abstract: ... Strikingly, E1047Q largely abolished Ca2+ and Mg2+ permeation, rendering TRPM7 a monovalent selective channel ... The channel kinases TRPM6 and TRPM7 have recently been discovered to play important roles in Mg2+ ... residues in the pore of TRPM6, E1024Q and E1029Q, produced nearly identical changes to the channel ...

    Abstract The channel kinases TRPM6 and TRPM7 have recently been discovered to play important roles in Mg2+ and Ca2+ homeostasis, which is critical to both human health and cell viability. However, the molecular basis underlying these channels' unique Mg2+ and Ca2+ permeability and pH sensitivity remains unknown. Here we have created a series of amino acid substitutions in the putative pore of TRPM7 to evaluate the origin of the permeability of the channel and its regulation by pH. Two mutants of TRPM7, E1047Q and E1052Q, produced dramatic changes in channel properties. The I-V relations of E1052Q and E1047Q were significantly different from WT TRPM7, with the inward currents of 8- and 12-fold larger than TRPM7, respectively. The binding affinity of Ca2+ and Mg2+ was decreased by 50- to 140-fold in E1052Q and E1047Q, respectively. Ca2+ and Mg2+ currents in E1052Q were 70% smaller than those of TRPM7. Strikingly, E1047Q largely abolished Ca2+ and Mg2+ permeation, rendering TRPM7 a monovalent selective channel. In addition, the ability of protons to potentiate inward currents was lost in E1047Q, indicating that E1047 is critical to Ca2+ and Mg2+ permeability of TRPM7, and its pH sensitivity. Mutation of the corresponding residues in the pore of TRPM6, E1024Q and E1029Q, produced nearly identical changes to the channel properties of TRPM6. Our results indicate that these two glutamates are key determinants of both channels' divalent selectivity and pH sensitivity. These findings reveal the molecular mechanisms underpinning physiological/pathological functions of TRPM6 and TRPM7, and will extend our understanding of the pore structures of TRPM channels.
    MeSH term(s) Amino Acid Substitution ; Animals ; Calcium/metabolism ; Cations, Divalent/metabolism ; Cell Line ; Cell Membrane Permeability/physiology ; Cell Survival ; Humans ; Hydrogen-Ion Concentration ; Ion Transport/physiology ; Magnesium/metabolism ; Mice ; Mutation, Missense ; Phosphotransferases/genetics ; Phosphotransferases/metabolism ; Protein-Serine-Threonine Kinases ; Structure-Activity Relationship ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism
    Chemical Substances Cations, Divalent ; TRPM Cation Channels ; TRPM6 protein, human ; Phosphotransferases (EC 2.7.-) ; Trpm7 protein, mouse (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; TRPM7 protein, human (EC 2.7.11.1) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2007-06-28
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M608972200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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