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Activation of the calcium-sensing receptor attenuates TRPV6-dependent intestinal calcium absorption
Justin J. Lee, … , Henrik Dimke, R. Todd Alexander
Justin J. Lee, … , Henrik Dimke, R. Todd Alexander
Published April 23, 2019
Citation Information: JCI Insight. 2019;4(11):e128013. https://doi.org/10.1172/jci.insight.128013.
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Research Article Gastroenterology Nephrology

Activation of the calcium-sensing receptor attenuates TRPV6-dependent intestinal calcium absorption

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Abstract

Plasma calcium (Ca2+) is maintained by amending the release of parathyroid hormone and through direct effects of the Ca2+-sensing receptor (CaSR) in the renal tubule. Combined, these mechanisms alter intestinal Ca2+ absorption by modulating 1,25-dihydroxyvitamin D3 production, bone resorption, and renal Ca2+ excretion. The CaSR is a therapeutic target in the treatment of secondary hyperparathyroidism and hypocalcemia, a common complication of calcimimetic therapy. The CaSR is also expressed in intestinal epithelium; however, a direct role in regulating local intestinal Ca2+ absorption is unknown. Chronic CaSR activation decreased expression of genes involved in Ca2+ absorption. In Ussing chambers, increasing extracellular Ca2+ or basolateral application of the calcimimetic cinacalcet decreased net Ca2+ absorption across intestinal preparations acutely. Conversely, Ca2+ absorption increased with decreasing extracellular Ca2+ concentration. These responses were absent in mice expressing a nonfunctional TRPV6, TRPV6D541A. Cinacalcet also attenuated Ca2+ fluxes through TRPV6 in Xenopus oocytes when coexpressed with the CaSR. Moreover, the phospholipase C inhibitor U73122 prevented cinacalcet-mediated inhibition of Ca2+ flux. These results reveal a regulatory pathway whereby activation of the CaSR in the basolateral membrane of the intestine directly attenuates local Ca2+ absorption via TRPV6 to prevent hypercalcemia and help explain how calcimimetics induce hypocalcemia.

Authors

Justin J. Lee, Xiong Liu, Debbie O’Neill, Megan R. Beggs, Petra Weissgerber, Veit Flockerzi, Xing-Zhen Chen, Henrik Dimke, R. Todd Alexander

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Figure 1

Relative intestinal mRNA expression of transcellular Ca2+ transport mediators under altered extracellular Ca2+ conditions.

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Relative intestinal mRNA expression of transcellular Ca2+ transport medi...
(A–C) Relative mRNA expression of transcellular Ca2+ transport mediators TRPV6 (Trpv6), CABP9K (S100g), NCX1 (Slc8a1), or PMCA1b (Atp2b1), normalized to 18S rRNA expression in mice on high-, normal- (Con), or low-Ca2+ diet for 21 days (n = 7 for each diet). (D–F) Relative mRNA expression in animals treated with 1,25-[OH]2 D3 (VD) or vehicle (Veh) (n = 8 for each). (G–I) Relative mRNA expression in animals treated with cinacalcet (Cin) or control (Veh) diet (n = 8 for each). All data are presented as the mean ± SEM, normalized to the mice on the normal/control diet. Asterisks indicate a statistically significant difference from the normal/control mice by 1-way ANOVA (all genes in A and Slc8a1 and Atp2b1 in B and C), Brown-Forsythe test (S100g in B), Kruskal-Wallis test (Trpv6 in B and C), or Student’s unpaired t tests (D–I); *P < 0.05, **P < 0.01, ***P < 0.001.
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