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Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone de Groot T; Kovalevskaya NV; Verkaart S; Schilderink N; Felici M; van der Hagen EA; Bindels RJ; Vuister GW; Hoenderop JGMol Cell Biol 2011[Jul]; 31 (14): 2845-53The epithelial Ca(2+) channel transient receptor potential vanilloid 5 (TRPV5) constitutes the apical entry gate for active Ca(2+) reabsorption in the kidney. Ca(2+) influx through TRPV5 induces rapid channel inactivation, preventing excessive Ca(2+) influx. This inactivation is mediated by the last approximately 30 residues of the carboxy (C) terminus of the channel. Since the Ca(2+)-sensing protein calmodulin has been implicated in Ca(2+)-dependent regulation of several TRP channels, the potential role of calmodulin in TRPV5 function was investigated. High-resolution nuclear magnetic resonance (NMR) spectroscopy revealed a Ca(2+)-dependent interaction between calmodulin and a C-terminal fragment of TRPV5 (residues 696 to 729) in which one calmodulin binds two TRPV5 C termini. The TRPV5 residues involved in calmodulin binding were mutated to study the functional consequence of releasing calmodulin from the C terminus. The point mutants TRPV5-W702A and TRPV5-R706E, lacking calmodulin binding, displayed a strongly diminished Ca(2+)-dependent inactivation compared to wild-type TRPV5, as demonstrated by patch clamp analysis. Finally, parathyroid hormone (PTH) induced protein kinase A (PKA)-dependent phosphorylation of residue T709, which diminished calmodulin binding to TRPV5 and thereby enhanced channel open probability. The TRPV5-W702A mutant exhibited a significantly increased channel open probability and was not further stimulated by PTH. Thus, calmodulin negatively modulates TRPV5 activity, which is reversed by PTH-mediated channel phosphorylation.|Amino Acid Sequence[MESH]|Calcium/metabolism[MESH]|Calmodulin/*metabolism[MESH]|Fluorescent Dyes/metabolism[MESH]|Fura-2/analogs & derivatives/metabolism[MESH]|HEK293 Cells[MESH]|Humans[MESH]|Molecular Sequence Data[MESH]|Nuclear Magnetic Resonance, Biomolecular[MESH]|Parathyroid Hormone/*metabolism[MESH]|Point Mutation[MESH]|Protein Binding[MESH]|TRPV Cation Channels/genetics/*metabolism[MESH] |
