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

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.