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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.
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Research Article Cell biology Endocrinology

Control of PTH secretion by the TRPC1 ion channel

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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

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Figure 3

Inactivation of the Trpc1 gene increases PTH secretion.

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Inactivation of the Trpc1 gene increases PTH secretion.
(A–C) Absolute P...
(A–C) Absolute PTH levels in media of WT PTH-C1 cells or cells lacking TRPC1 in the presence or absence of exogenously transfected PTH. *P < 0.05; ***P < 0.001, Student’s t test. (D) TRPC1 topology and location of F689. Pore-forming region connecting S5 and S6 is shown in red. Ankyrin repeats are shown as dark green cylinders and pre-S1 and TRP-box domains as shown are red cylinders. (E) Readdition of WT mouse TRPC1α but not the TRPC1αF689A pore mutant rescues suppressed PTH secretion in cells lacking endogenous rat TRPC1 (PTH-C1PTH-2/Trpc1-KO) cells. Data from 9–18 measurements were pooled from 3–6 independent experiments. **P < 0.01, 1-way ANOVA. (F) Spermine-induced changes in free intracellular Ca2+ in HEK293 cells transiently cotransfected with CaSR plus WT TRPC1α (black, n = 296 cells pooled from 3 experiments) or TRPC1α-F689A (red, n = 276 cells pooled from 3 experiments).

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