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Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation de Groot T; Lee K; Langeslag M; Xi Q; Jalink K; Bindels RJ; Hoenderop JGJ Am Soc Nephrol 2009[Aug]; 20 (8): 1693-704Low extracellular calcium (Ca(2+)) promotes release of parathyroid hormone (PTH), which acts on multiple organs to maintain overall Ca(2+) balance. In the distal part of the nephron, PTH stimulates active Ca(2+) reabsorption via the adenylyl cyclase-cAMP-protein kinase A (PKA) pathway, but the molecular target of this pathway is unknown. The transient receptor potential vanilloid 5 (TRPV5) channel constitutes the luminal gate for Ca(2+) entry in the distal convoluted tubule and has several putative PKA phosphorylation sites. Here, we investigated the effect of PTH-induced cAMP signaling on TRPV5 activity. Using fluorescence resonance energy transfer, we studied cAMP and Ca(2+) dynamics during PTH stimulation of HEK293 cells that coexpressed the PTH receptor and TRPV5. PTH increased cAMP levels, followed by a rise in TRPV5-mediated Ca(2+) influx. PTH (1 to 31) and forskolin, which activate the cAMP pathway, mimicked the stimulation of TRPV5 activity. Remarkably, TRPV5 activation was limited to conditions of strong intracellular Ca(2+) buffering. Cell surface biotinylation studies demonstrated that forskolin did not affect TRPV5 expression on the cell surface, suggesting that it alters the single-channel activity of a fixed number of TRPV5 channels. Application of the PKA catalytic subunit, which phosphorylated TRPV5, directly increased TRPV5 channel open probability. Alanine substitution of threonine-709 abolished both in vitro phosphorylation and PTH-mediated stimulation of TRPV5. In summary, PTH activates the cAMP-PKA signaling cascade, which rapidly phosphorylates threonine-709 of TRPV5, increasing the channel's open probability and promoting Ca(2+) reabsorption in the distal nephron.|*Calcium Signaling[MESH]|Calcium/*metabolism[MESH]|Cell Line[MESH]|Colforsin[MESH]|Cyclic AMP-Dependent Protein Kinases/*metabolism[MESH]|Cyclic AMP/metabolism[MESH]|Fluorescence Resonance Energy Transfer[MESH]|Humans[MESH]|Parathyroid Hormone/*metabolism[MESH]|Phosphatidylinositol 4,5-Diphosphate/metabolism[MESH]|Phosphorylation[MESH]|Receptor, Parathyroid Hormone, Type 1/metabolism[MESH]|TRPV Cation Channels/*metabolism[MESH]|Threonine[MESH] |
