Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Control of PTH secretion by the TRPC1 ion channel
Marta Onopiuk, … , Leonidas Tsiokas, Kai Lau
Marta Onopiuk, … , Leonidas Tsiokas, Kai Lau
Published March 26, 2020
Citation Information: JCI Insight. 2020;5(8):e132496. https://doi.org/10.1172/jci.insight.132496.
View: Text | PDF
Research Article Cell biology Endocrinology

Control of PTH secretion by the TRPC1 ion channel

  • Text
  • PDF
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.

Authors

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

×

Figure 2

Parathyroid glands lacking TRPC1 fail to properly control PTH secretion.

Options: View larger image (or click on image) Download as PowerPoint
Parathyroid glands lacking TRPC1 fail to properly control PTH secretion....
(A) TRPC1 is widely expressed in normal mouse PTGs. Top: H&E staining of Trpc1+/+ (left) and Trpc1–/– (right) glands. Bottom: Expression of TRPC1 in WT (left) and Trpc1-null (right) PTGs by immunohistochemistry using a mouse monoclonal antibody against TRPC1 (1F1). Original magnification, ×40. (B) Responses of PTH release at different [Ca2+]e (pg/30 min/gland) in PTGs isolated from 8 (3 males and 5 females) WT and 8 (3 males and 5 females) 14-week-old Trpc1-null mice. (C) Ca2+ dose-response curves shown in B were normalized and are expressed as a percentage of the PTH release at 0.5 mM Ca2+. Perpendicular lines depict Ca2+ set points (1.04 mM ± 0.15 for Trpc1+/+ and 1.25 mM ± 0.08 for Trpc1–/– mice).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts