Back to Search
Start Over
Phosphorylated claudin-16 interacts with Trpv5 and regulates transcellular calcium transport in the kidney.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Sep 17; Vol. 116 (38), pp. 19176-19186. Date of Electronic Publication: 2019 Sep 05. - Publication Year :
- 2019
-
Abstract
- Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was previously considered to be a paracellular channelopathy caused by mutations in the claudin-16 and claudin-19 genes. Here, we provide evidence that a missense FHHNC mutation c.908C>G (p.T303R) in the claudin-16 gene interferes with the phosphorylation in the claudin-16 protein. The claudin-16 protein carrying phosphorylation at residue T303 is localized in the distal convoluted tubule (DCT) but not in the thick ascending limb (TAL) of the mouse kidney. The phosphomimetic claudin-16 protein carrying the T303E mutation but not the wildtype claudin-16 or the T303R mutant protein increases the Trpv5 channel conductance and membrane abundance in human kidney cells. Phosphorylated claudin-16 and Trpv5 are colocalized in the luminal membrane of the mouse DCT tubule; phosphomimetic claudin-16 and Trpv5 interact in the yeast and mammalian cell membranes. Knockdown of claudin-16 gene expression in transgenic mouse kidney delocalizes Trpv5 from the luminal membrane in the DCT. Unlike wildtype claudin-16, phosphomimetic claudin-16 is delocalized from the tight junction but relocated to the apical membrane in renal epithelial cells because of diminished binding affinity to ZO-1. High-Ca <superscript>2+</superscript> diet reduces the phosphorylation of claudin-16 protein at T303 in the DCT of mouse kidney via the PTH signaling cascade. Knockout of the PTH receptor, PTH1R, from the mouse kidney abrogates the claudin-16 phosphorylation at T303. Together, these results suggest a pathogenic mechanism for FHHNC involving transcellular Ca <superscript>2+</superscript> pathway in the DCT and identify a molecular component in renal Ca <superscript>2+</superscript> homeostasis under direct regulation of PTH.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Calcium Channels genetics
Cell Membrane Permeability
Claudins antagonists & inhibitors
Claudins genetics
HEK293 Cells
Humans
Male
Mice
Mice, Knockout
Phosphorylation
TRPV Cation Channels antagonists & inhibitors
TRPV Cation Channels genetics
Calcium metabolism
Calcium Channels metabolism
Claudins metabolism
Kidney Tubules, Distal metabolism
TRPV Cation Channels metabolism
Tight Junctions metabolism
Transcytosis
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 116
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 31488724
- Full Text :
- https://doi.org/10.1073/pnas.1902042116