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

Abstract

A novel mechanism is shown by which TRPV5 and Ca2+ reabsorption by the kidney is regulated. This supports the idea that histidine phosphorylation plays other, yet-uncovered roles in mammalian biology.

Advances in development of new tools for the study of phosphohistidine

“…Two isoforms of nucleoside diphosphate kinase (NDPK): Nme1/NDPK-A [9][10][11][12][13] and Nme2/NDPK-B [14][15][16][17][18][19] have been characterized as mammalian His kinases. Other mammalian His kinases exist.…”

“…28 In this particular case, it is not clear which isomer of pHis is formed and on which His residue. Mammalian pHis phosphatases, which have been characterized include: protein pHis phosphatase 1 (PHPT1); 17,[29][30][31][32][33][34][35] Lys/His phosphatase (LHPPase); 36,37 Ser Thr protein phosphatases (PP1/2 A/2C); 38,39 T-cell ubiquitin ligand-2 (TULA-2); 40,41 and the recently reported phosphoglycerate mutase-5 (PGAM5). 42 In addition, pHis phosphatase activity has been reported in rat tissue extracts but these have not been fully characterized.…”

“…[43][44][45][46] Not only is His phosphorylation predicted to be prevalent in eukaryotic proteins, 38 it has also been associated with important mammalian cellular processes. For example, pHis has been shown to be present in heteromeric G proteins (GNB1), which are involved in G protein signalling, 15,47,48 KCa3.1 potassium channel, which is involved in ion conductance, 18,49 ATP-citrate lyase (ACLY), which is involved in cell metabolism, 9 histone H4, which is involved in chromatin biology, 21,22,28 transient receptor potentialvanilloid-5 (TRPV5), which regulates urinary Ca 2+ excretion, 17 and phosphoglycerate mutase 1 (PGAM1), which is involved in glycolysis. [50][51][52][53] Other mammalian pHis proteins include P-selectin, which has an important role in the function of blood platelets, 54 annexin A1 a multi-functional Ca 2+ -dependant phospholipid-binding protein found in airway epithelia cells, 55 thymidylate synthase, which catalyzes Nmethylenetetrahydrofolate assisted C(5)-methylation of dUMP required for DNA synthesis, 56 glucose-6-phosphatase involved in glucose homeostasis, 57,58 nicotinamide phosphotransferase (NAMTP) involved in reforming nicotinamide adenine dinucleotide (NAD + ) from nicotinamide 59 and prostatic acid phosphatase, which is found in high levels in prostate cancer cells.…”

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

“…27,28 For example, besides Gβ subunit modulation, NDPK-B-mediated histidine phosphorylation activates the small-conductance Ca 2+ -activated K + channel K Ca 3.1 29 and the transient receptor potential Ca 2+ channel TRPV5. 30 The phosphorylation of a histidine residue involves bonding of a phosphoryl group to the imidazole ring of the histidine through a phosphoramidate bond. As this imidazole ring has two nitrogen atoms, multiple forms of phosphorylation involving the N1 (1-pHis) or N3 (3-pHis) position are possible.…”

Nucleoside diphosphate kinases (NDPKs) in animal development

“…excretion a Ca 2? -permeable channel, the transient receptor potential-vanilloid-5 (TRPV5) channel was found to be phosphorylated and thus activated by NME2 [109]. Experiments performed on fibroblasts of Nme1 -/-/ Nme2 -/-knockout mice and zebrafish show that NME2 influences heterotrimeric G protein signaling through phosphorylation of Gbc dimers, thereby stimulating cardiac contractility [104].…”