Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/23675
Title: Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone.
Authors: de Groot T
Kovalevskaya, NV
Verkaart, S
Schilderink, N
Felici, M
van der Hagen EA
Bindels, RJ
Vuister, GW
Hoenderop, JG
First Published: Jul-2011
Citation: MOL CELL BIOL, 2011, 31 (14), pp. 2845-2853
Abstract: The 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 ∼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.
DOI Link: 10.1128/MCB.01319-10
eISSN: 1098-5549
Links: http://hdl.handle.net/2381/23675
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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