Control of PTH secretion by the TRPC1 ion channel

Journal article

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 CaSR encoding the Ca2+ sensing receptor (CaSR), a G protein coupled receptor (GPCR) and GNA11 encoding G protein subunit alpha 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 reveal that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTG) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacts with both the N- and C-termini of TRPC1 and enhances 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: Onopiuk, M; Eby, B; Nesin, V; Lerner, M; Ngo, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Clinical Investigation
• Journal: JCI insight
• Volume: 5
• Issue: 8
• Article number: e132496
• Publication date: 2020-03-26
• Acceptance date: 2020-03-16
• DOI: 10.1172/jci.insight.132496
• EISSN: 2379-3708
• ISSN: 2379-3708
• Pmid: 32213715
• Language: English
• Keywords: calcium; FFR; endocrinology; cell biology