title: Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1.
abstract: The kidney, together with bone and intestine, plays a crucial role in maintaining whole-body calcium (Ca(2+)) homoeostasis, which is primarily mediated by altering the reabsorption of Ca(2+) filtered by the glomerulus. The transient receptor potential-vanilloid-5 (TRPV5) channel protein forms a six- transmembrane Ca(2+)-permeable channel that regulates urinary Ca(2+) excretion by mediating active Ca(2+) 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 Ca(2+) 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 Ca(2+) reabsorption in vivo, as short hairpin RNA knockdown of NDPK-B leads to decreased TRPV5 channel activity, and urinary Ca(2+) excretion is increased in NDPK-B(-/-) mice fed a high-Ca(2+) diet. Thus these findings identify a novel mechanism by which TRPV5 and Ca(2+) reabsorption is regulated by the kidney and support the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.
authors: Division of Nephrology, New York University Langone Medical Center, New York, NY 10016 Department of Molecular Pathogenesis, New York University Langone Medical Center, New York, NY 10016 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 Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016.
authors: Xinjiang
authors: X
authors: Cai
authors: Shekhar
authors: S
authors: Srivastava
authors: Sheena
authors: S
authors: Surindran
authors: Zhai
authors: Z
authors: Li
authors: Edward Y
authors: EY
authors: Skolnik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D004285:Dogs; D057809:HEK293 Cells; D006639:Histidine / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D016415:Sequence Alignment; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C492239:TRPV5 protein, human; D006639:Histidine; D009701:Nucleoside-Diphosphate Kinase; C542596:NDPK-B protein, human; C504019:PHPT1 protein, human; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium