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Published on: December 31, 2013
Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation
Theun de Groot1, Kyupil Lee, Michiel Langeslag
1Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Summary
Parathyroid hormone (PTH) activates calcium reabsorption in the kidney by stimulating the cAMP-PKA pathway. This pathway phosphorylates the TRPV5 channel at threonine-709, increasing its open probability and enhancing calcium uptake.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Physiology
Background:
- Low extracellular calcium (Ca2+) triggers parathyroid hormone (PTH) release to maintain Ca2+ homeostasis.
- PTH stimulates Ca2+ reabsorption in the distal nephron via the adenylyl cyclase-cAMP-protein kinase A (PKA) pathway.
- The precise molecular target of PTH-induced cAMP-PKA signaling in Ca2+ reabsorption remains unidentified.
Purpose of the Study:
- To investigate the effect of PTH-induced cAMP signaling on the activity of the transient receptor potential vanilloid 5 (TRPV5) channel.
- To determine if TRPV5 is the molecular target of the PTH-activated cAMP-PKA pathway in renal Ca2+ reabsorption.
Main Methods:
- Utilized fluorescence resonance energy transfer (FRET) to monitor cAMP and Ca2+ dynamics in HEK293 cells coexpressing the PTH receptor and TRPV5.
- Employed cell surface biotinylation assays to assess TRPV5 surface expression.
- Applied the catalytic subunit of PKA and performed site-directed mutagenesis (T709A) on TRPV5.
Main Results:
- PTH stimulation led to increased intracellular cAMP levels, followed by enhanced TRPV5-mediated Ca2+ influx.
- Forskolin and PTH (1-31) mimicked the stimulatory effect on TRPV5 activity, independent of changes in cell surface expression.
- Direct phosphorylation of TRPV5 by PKA increased its open probability, with T709 identified as the critical phosphorylation site.
Conclusions:
- PTH activates the cAMP-PKA signaling cascade in the distal nephron.
- The TRPV5 channel is a key molecular target of this cascade, with phosphorylation at T709 enhancing its activity.
- This mechanism promotes Ca2+ reabsorption, contributing to overall calcium balance.
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