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

Mol Biol Cell. 2014 Apr;25(8):1244-50. doi: 10.1091/mbc.E13-04-0180. Epub 2014 Feb 12.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calcium Signaling
  • Cell Line
  • Dogs
  • HEK293 Cells
  • Histidine / metabolism
  • Homeostasis
  • Humans
  • Kidney Glomerulus / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleoside-Diphosphate Kinase / genetics
  • Nucleoside-Diphosphate Kinase / metabolism
  • Patch-Clamp Techniques
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering
  • Sequence Alignment
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*


  • Calcium Channels
  • RNA, Small Interfering
  • TRPV Cation Channels
  • TRPV5 protein, human
  • Histidine
  • Nucleoside-Diphosphate Kinase
  • NDPK-B protein, human
  • PHPT1 protein, human
  • Phosphoric Monoester Hydrolases
  • Calcium