Control of PTH secretion by the TRPC1 ion channel

Research output: Contribution to journalArticle

Authors

  • Marta Onopiuk
  • Bonnie Eby
  • Vasyl Nesin
  • Peter Ngo
  • Megan Lerner
  • Victoria J Stokes
  • Rajesh V Thakker
  • Maria Luisa Brandi
  • Wenhan Chang
  • Mary Beth Humphrey
  • Leonidas Tsiokas
  • Kai Lau

Colleges, School and Institutes

External organisations

  • Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, D53121 Bonn, Germany
  • Department of Medicine, Vanderbilt University School of Medicine
  • The University of Oklahoma Health Sciences Center
  • Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Oncology, University of Oxford, Oxford, UK.
  • Department of Biomedicals Sperimentals and Clinicals Sciences

Abstract

Familial hypocalciuric hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia, and, in some cases, inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in the gene encoding the Ca2+-sensing receptor (CaSR), a GPCR, and GNA11 encoding G protein subunit α 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels, mimicking human FHH. Ex vivo and in vitro studies revealed that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTGs) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacted with both the N- and C-termini of TRPC1 and enhanced CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR.

Details

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalJCI Insight
Volume5
Issue number8
Early online date26 Mar 2020
Publication statusPublished - 23 Apr 2020