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

Lee, Justin J; Liu, Xiong; Oneill, D.M.; Beggs, Megan R; Weißgerber, Petra; Flockerzi, Veit; Chen, Xing-Zhen; Dimke, Henrik; Alexander, R. Todd

doi:10.1172/jci.insight.128013

Cited by 30 publications

(30 citation statements)

References 76 publications

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“…mRNA probes and antibodies have revealed that the CaSR is widely expressed both in tissues directly involved in controlling systemic Ca 2+ o homeostasis as well as in tissues with other functions. As detailed in the section, V. (Patho)physiology of the Calcium-Sensing Receptor and Its Ligands, the plasma calcium level is mainly regulated via actions on the parathyroid gland (PTH release), thyroid gland (calcitonin release, although calcitonin in humans is less important than in rodents), and kidney (production of 1,25(OH) 2 D 3 and regulation of ion excretion), but other tissues, such as the bone (release of skeletal Ca 2+ o ) and small intestine (Ca 2+ o absorption), also play a role both via direct CaSR activation and via PTH, calcitonin, and 1,25(OH) 2 D 3 (Brown and MacLeod, 2001;Brown, 2013;Lee et al, 2019). In addition, the CaSR is expressed in a range of tissues not involved in systemic Ca 2+ o homeostasis, such as the keratinocytes of the skin (VE.…”

Section: Tissue Distributionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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Section: Tissue Distributionmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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“…These data are consistent with the unaltered fractional excretion of Ca 2+ observed and indicate that at the lower plasma Ca 2+ levels in the Nuf/+ and Nuf/Nuf mice, activation of the renal CaSR does not occur. Similarly, we have shown that activation of the intestinal CaSR in the duodenum and colon attenuates transcellular Ca 2+ absorption by inhibiting TRPV6 activity and Trpv6 expression (10). We therefore looked at the expression of genes mediating transcellular calcium absorption in these tissues.…”

Section: Renal and Intestinal Casrs Are Not Activated In Nuf Micementioning

confidence: 99%

“…In fact, CaSR activation in the kidney plays a crucial role in the defense against hypercalcemia (9). Furthermore, we have found that CaSR activation in the intestine decreases the expression of the epithelial Ca 2+ channel transient receptor potential vanilloid 6 (TRPV6), thereby attenuating intestinal Ca 2+ absorption (10). Thus, activation of the CaSR in the kidney and intestine limits Ca 2+ transport in these tissues by regulating the expression of CaSR-sensitive genes.…”

Section: Introductionmentioning

confidence: 98%

Differential activation of parathyroid and renal Ca²⁺-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1

Megen

Tan

Alexander

et al. 2021

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Background Parathyroid Ca2+-sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of CaSRs in kidneys and intestine attenuates local transepithelial Ca2+ transport. In patients with autosomal dominant hypocalcemia 1 (ADH1) due to activating CASR mutations, treatment of symptomatic hypocalcemia can be complicated by treatment-induced hypercalciuria, resulting in nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body are activated by increased extracellular Ca2+ concentrations, it is not understood why some ADH1 patients have reduced PTH, but not hypercalciuria at presentation, despite CaSR expression in both kidney and parathyroid. Methods Activation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells. Results Mice with a gain-of-function mutation in Casr are hypocalcemic with reduced plasma PTH levels. However, renal CaSRs are not activated as indicated by normal urinary calcium handling and unaltered renal Cldn14 expression. Activation of renal CaSRs only occurred after increasing plasma Ca2+ levels. Similarly, calcimimetic administration to wildtype mice induced hypocalcemia without activating renal CaSRs. Moreover, significant hypercalciuria was not observed in an ADH1 patient until blood Ca2+ was normalized. In vitro experiments suggest that increased CaSR levels in the parathyroid relative to the kidney contribute tissue-specific CaSR activation thresholds. Conclusion Here we delineate tissue-specific CaSR activation thresholds, where parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even with overactivating mutations. These findings may aid in the management of ADH1 patients.

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“…Transcellular Ca 2+ absorption is adenosine triphosphate dependent and mediated by the apical membrane calcium channel TRPV6 (also known as CaT1 or ECaC2), basolateral sodium-calcium exchanger (NCX) 1, the plasma membrane calcium pump (PMCA) 1b, and the intracellular calcium binding protein S100-G (calbindin-D 9k , known as CaBP). Transcription of Trpv6 and S100g is increased by the vitamin D metabolite 1,25-[OH] 2 D 3 , indicating hypocalcemia, and is suppressed by the extracellular Ca 2+ receptor (CaSR) activation, indicative of hypercalcemia in the duodenum and proximal colon of mice 2, 3. Jejunal calcium absorption has been found through apical L-type Ca 2+ channel(s), such as Ca v1.3 , and is enhanced by high concentrations of glucose in rats 4 .…”

mentioning

confidence: 99%

“…While molecular techniques such as in situ hybridization and immunohistochemistry have aided in the identification of nutrient transporters and their segmental heterogeneity, the Alexander group3, 5 has employed the Ussing chamber system (ex vivo). This classic electrophysiological assay is suited to quantifying transporter functions, especially in the transcellular pathway under voltage-clamping (short-circuit) conditions and is able to simultaneously compare diverse regions.…”

mentioning

confidence: 99%

Dynamics of Intestinal Calcium Absorption in Neonates

Kaji

2019

Cellular and Molecular Gastroenterology and Hepatology

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

Cited by 30 publications

References 76 publications

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Differential activation of parathyroid and renal Ca²⁺-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1

Dynamics of Intestinal Calcium Absorption in Neonates

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

Cited by 30 publications

References 76 publications

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Differential activation of parathyroid and renal Ca2+-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1

Dynamics of Intestinal Calcium Absorption in Neonates

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Differential activation of parathyroid and renal Ca²⁺-sensing receptors underlies the renal phenotype in autosomal dominant hypocalcemia 1