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Activation of the Calcium-Sensing Receptor Attenuates TRPV6- Dependent Intestinal Calcium Absorption

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Activation of the Calcium-Sensing Receptor Attenuates TRPV6- Dependent Intestinal Calcium Absorption Activation of the calcium-sensing receptor attenuates TRPV6- dependent intestinal calcium absorption Justin J. Lee, … , Henrik Dimke, R. Todd Alexander JCI Insight. 2019;4(11):e128013. https://doi.org/10.1172/jci.insight.128013. Research Article Gastroenterology Nephrology 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 2+ modulating 1,25-dihydroxyvitamin D3 production, bone resorption, and renal Ca 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. Find the latest version: https://jci.me/128013/pdf RESEARCH ARTICLE Activation of the calcium-sensing receptor attenuates TRPV6-dependent intestinal calcium absorption Justin J. Lee,1,2 Xiong Liu,1 Debbie O’Neill,1 Megan R. Beggs,1,2 Petra Weissgerber,3 Veit Flockerzi,3 Xing-Zhen Chen,1 Henrik Dimke,4,5 and R. Todd Alexander1,2,6 1Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. 2The Women’s and Children’s Health Research Institute, Edmonton, Alberta, Canada. 3Experimentelle und Klinische Pharmakologie und Toxikologie, Saarland University, Hamburg, Germany. 4Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 5Department of Nephrology, Odense University Hospital, Odense, Denmark. 6Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 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 2+ alter intestinal Ca 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. Introduction Calcium (Ca2+) homeostasis is vital to many physiological functions and is thus tightly regulated by altering Ca2+ transport across intestine, kidneys, and bone. It has been appreciated for some time that endocrine hormones, 2+ including parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-[OH]2 D3), alter Ca transport across the intestine and kidneys or aid mobilization from bone (1–4). However, more recently, the homeostatic mechanisms permitting direct sensing of extracellular Ca2+ by the nephron or bone and subsequently altering tubular Ca2+ reabsorption or bone remodeling were delineated (5, 6). This direct sensing of extracellular Ca2+ occurs, at least in part, by the 7-transmembrane G protein–coupled Ca2+ sensing receptor (CaSR) (7). Conflict of interest: RTA has PTH release from the parathyroid gland increases plasma Ca2+ levels through direct effects on the nephron consulted for Ardylex Inc. and and bone and indirect effects on the intestine via stimulation of renal CYP27B1 activity, which catalyzes the Advicenne Inc. 2+ synthesis of 1,25-[OH]2 D3 (8–11). PTH secretion is regulated by the CaSR, where increased extracellular Ca © 2019 American Society Copyright: activates the receptor, inhibiting release of PTH (12–14) and hence formation of 1,25-[OH]2 D3. In the thick for Clinical Investigation ascending limb (TAL), blood Ca2+ concentration is also sensed by the basolateral CaSR, which directly signals to 2+ 2+ Submitted: February 7, 2019 decrease Ca reabsorption in that nephron segment (15–18). Conversely, PTH stimulates Ca absorption from Accepted: April 17, 2019 the TAL (18, 19) and transcellular Ca2+ reabsorption from the distal convoluted tubule (DCT) and connecting Published: June 6, 2019. tubule (CNT) (20–22). These studies highlight how the renal tubule both responds to endocrine regulation, and 2+ 2+ Reference information: JCI Insight. directly senses extracellular Ca , to amend Ca reabsorption, thereby preventing hypercalcemia. 2019;4(11):e128013. https://doi. The duodenum, cecum, and proximal colon are sites of significant intestinal transcellular Ca2+ absorption org/10.1172/jci.insight.128013. (23, 24). Transcellular Ca2+ transport is a unidirectional, ATP-driven process mediated, at least in part, by the insight.jci.org https://doi.org/10.1172/jci.insight.128013 1 RESEARCH ARTICLE 2+ apically expressed channel TRPV6, the intracellular Ca -buffering protein calbindin-D9k (CABP9K), and the basolateral Ca2+-extruding proteins plasma membrane Ca2+ ATPase 1b (PMCA1b) and Na+/Ca2+-exchanger (NCX1) (23). Hypocalcemia leads to increased PTH secretion, which stimulates the production of 1,25-[OH]2 2+ 2+ D3 and thus increases intestinal Ca transport (8–11). 1,25-[OH]2 D3 increases intestinal Ca absorption by increasing the expression of TRPV6, a phenomenon that correlates with intestinal Ca2+ absorption (24–26). The resulting increased Ca2+ influx in turn enhances the expression of CABP9K (27–29). Conversely, hypercalcemia 2+ inhibits PTH release and consequently reduces intestinal Ca uptake, by limiting active 1,25-[OH]2 D3 synthesis. However, this latter regulatory mechanism would be rather slow with respect to attenuating hypercalcemia. The CaSR is expressed throughout the intestine (30–32), where it regulates fluid, sodium, and chloride secretion (32–34). However, a direct role in Ca2+ homeostasis has not been reported (7, 33). We hypoth- esized that the intestinal CaSR has a functional role in maintaining Ca2+ homeostasis, where it detects extracellular Ca2+ levels and directly alters transcellular Ca2+ absorption across the sensing intestinal epi- thelium in response. To test our hypothesis, we first examined the expression of transcellular Ca2+-trans- porting proteins following chronic CaSR activation and found decreased expression of genes known to facilitate transcellular Ca2+ absorption across the intestine. We further observed that acute pharmacological or physiological activation of a basolateral CaSR in intestinal epithelium ex vivo attenuated transcellular Ca2+ absorption. Moreover, this attenuation was absent in transgenic mice expressing functionally inactive TRPV6 Ca2+ channels. Together, our results demonstrate that basolateral activation of an intestinal CaSR directly inhibits local Ca2+ absorption from that intestinal segment via TRPV6. Results Activation of an intestinal CaSR decreases expression of genes involved in transcellular Ca2+ absorption. The expres- sion of genes mediating transcellular Ca2+ absorption was measured on intestinal tissue from FVB/N mice fed a low (0.01%), normal (0.6%), or high (2%) Ca2+ diet for 21 days. Trpv6 mRNA expression was increased in mice fed a low-Ca2+ diet, with the greatest, greater than 30-fold increase, observed in the prox- imal colon (Figure 1A). A high-Ca2+ diet suppressed Trpv6 expression in the duodenum, cecum, and proxi- 2+ mal colon, perhaps because of low 1,25-[OH]2 D3, although a direct inhibitory effect of plasma Ca cannot be excluded. The same relationship, between increased dietary Ca2+ content and reduced gene expression, was observed for S100g, which encodes the intracellular Ca2+-buffering and -shuttling protein CABP9K. The mRNA expression of the basolateral Ca2+ efflux transporters NCX1 Slc8a1( ) and PMCA1b (Atp2b1) were unaltered in all tissues under different dietary calcium–containing conditions (Figure 1, A–C). The serum Ca2+ of mice fed altered-Ca2+ diets
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