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The selectivity filter of the cation channel TRPM4 Nilius B; Prenen J; Janssens A; Owsianik G; Wang C; Zhu MX; Voets TJ Biol Chem 2005[Jun]; 280 (24): 22899-906Transient receptor potential channel melastatin subfamily (TRPM) 4 and its close homologue, TRPM5, are the only two members of the large transient receptor potential superfamily of cation channels that are impermeable to Ca(2+). In this study, we located the TRPM4 selectivity filter and investigated possible structural elements that render it Ca(2+)-impermeable. Based on homology with known cation channel pores, we identified an acidic stretch of six amino acids in the loop between transmembrane helices TM5 and TM6 ((981)EDMDVA(986)) as a potential selectivity filter. Substitution of this six-amino acid stretch with the selectivity filter of TRPV6 (TIIDGP) resulted in a functional channel that combined the gating hallmarks of TRPM4 (activation by Ca(2+), voltage dependence) with TRPV6-like sensitivity to block by extracellular Ca(2+) and Mg(2+) as well as Ca(2+) permeation. Neutralization of Glu(981) resulted in a channel with normal permeability properties but a strongly reduced sensitivity to block by intracellular spermine. Neutralization of Asp(982) yielded a functional channel that exhibited extremely fast desensitization (tau < 5 s), possibly indicating destabilization of the pore. Neutralization of Asp(984) resulted in a non-functional channel with a dominant negative phenotype when coexpressed with wild type TRPM4. Combined neutralization of all three acidic residues resulted in a functional channel whose voltage dependence was shifted toward very positive potentials. Substitution of Gln(977) by a glutamate, the corresponding residue in divalent cation-permeable TRPM channels, altered the monovalent cation permeability sequence and resulted in a pore with moderate Ca(2+) permeability. Our findings delineate the selectivity filter of TRPM channels and provide the first insight into the molecular basis of monovalent cation selectivity.|Alanine/chemistry[MESH]|Amino Acid Sequence[MESH]|Biotinylation[MESH]|Calcium Channels/*chemistry[MESH]|Calcium/chemistry/metabolism[MESH]|Cation Transport Proteins/*chemistry[MESH]|Cations[MESH]|Cell Line[MESH]|Electrophysiology[MESH]|Gene Deletion[MESH]|Genes, Dominant[MESH]|Glutamic Acid/chemistry[MESH]|Green Fluorescent Proteins/metabolism[MESH]|Humans[MESH]|Inhibitory Concentration 50[MESH]|Magnesium/chemistry[MESH]|Membrane Proteins/chemistry[MESH]|Models, Molecular[MESH]|Molecular Sequence Data[MESH]|Mutagenesis, Site-Directed[MESH]|Mutation[MESH]|Phenotype[MESH]|Protein Conformation[MESH]|Protein Structure, Secondary[MESH]|Protein Structure, Tertiary[MESH]|Sequence Homology, Amino Acid[MESH]|TRPM Cation Channels[MESH]|Time Factors[MESH] |
