Regulation of the epithelial Ca2+ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1

Author:

Cai Xinjiang123,Srivastava Shekhar123,Surindran Sheena123,Li Zhai123,Skolnik Edward Y.1234

Affiliation:

1. Division of Nephrology, New York University Langone Medical Center, New York, NY 10016

2. Department of Molecular Pathogenesis, New York University Langone Medical Center, New York, NY 10016

3. The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016

4. Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016

Abstract

The kidney, together with bone and intestine, plays a crucial role in maintaining whole-body calcium (Ca2+) homoeostasis, which is primarily mediated by altering the reabsorption of Ca2+ filtered by the glomerulus. The transient receptor potential-vanilloid-5 (TRPV5) channel protein forms a six- transmembrane Ca2+-permeable channel that regulates urinary Ca2+ excretion by mediating active Ca2+ reabsorption in the distal convoluted tubule of the kidney. Here we show that the histidine kinase, nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca2+ flux, and this activation requires histidine 711 in the carboxy-terminal tail of TRPV5. In addition, the histidine phosphatase, protein histidine phosphatase 1, inhibits NDPK-B–activated TRPV5 in inside/out patch experiments. This is physiologically relevant to Ca2+ reabsorption in vivo, as short hairpin RNA knockdown of NDPK-B leads to decreased TRPV5 channel activity, and urinary Ca2+ excretion is increased in NDPK-B−/− mice fed a high-Ca2+ diet. Thus these findings identify a novel mechanism by which TRPV5 and Ca2+ reabsorption is regulated by the kidney and support the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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