Cell surface, Ca2+(cation)-sensing receptor(s): one or many?

doi:10.1054/ceca.1999.0066

Cell Calcium

Volume 26, Issues 3–4, September 1999, Pages 77-83

https://doi.org/10.1054/ceca.1999.0066 Get rights and content

Abstract

In mammals Ca²⁺concentration in the extracellular fluids ([Ca²⁺]_o) is essential for a number of vital processes varying from bone mineralization to blood coagulation, regulation of enzymatic processes, modulation of permeability and excitability of plasma membranes. For this reason [Ca²⁺]_ois under strict control of a complex homeostatic system that includes parathyroid glands, kidneys, bones and intestine. The extracellular Ca²⁺-sensing receptor (CaR) is an essential component of this system, regulating parathyroid hormone secretion, calcium (and magnesium) excretion by the kidney, bone remodeling and Ca²⁺reabsorption by the gastrointestinal tract. Structurally, the CaR is a novel member of a growing G protein-coupled receptor superfamily, which includes metabotropic glutamate receptors (mGluRs) [1], [γ]-aminoisobutyric acid (GABA-B) receptors [2] and vomeronasal organ receptors [3]. Initially identified from bovine parathyroid glands [4], within the 5 years following its identification CaR presence has rapidly been identified as extending to organs where the link with mineral ion metabolism has not been elucidated (i.e. brain, stomach, eye, skin and many other epithelial cells) (see [5] for review). The role of the receptor in these regions is largely unknown, but it appears to be somewhat related to phenomena such as chemotaxis, cell proliferation and programmed cell death. This review will describe the discovery of a novel class of ion-sensing receptor(s), receptor–effector coupling and the roles of the CaR inside and outside the Ca²⁺_ohomeostatic system.

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This study was conducted to determine dietary calcium (Ca) requirement of bullfrog (Lithobates catesbeiana). Six diets were formulated to contain 0.55% (control), 0.96%, 1.30%, 1.72%, 2.02% and 2.53% Ca. Each diet was fed to triplicate tanks of bullfrogs (24.96 ± 0.03 g), and each tanks was stocked with 13 bullfrogs. Bullfrogs were fed twice daily (8:30 and 17:30) to apparent satiation for 8 weeks. Weight gain rate of bullfrogs fed the 1.72% Ca diet was significantly higher than the control group (P < 0.05). The content of Ca was significantly increased in the whole body and vertebrae of bullfrogs fed the 1.72%, 2.02% and 2.53% diets compared to those fed the 0.55%, 0.96% and 1.30% Ca diets (P < 0.05). Furthermore, bullfrogs fed the 1.30%, 1.72% and 2.02% diets had higher activity of trypsin than those fed the 0.55% and 2.53% Ca diets (P < 0.05). Apparent digestibility coefficient of dry matter was higher in bullfrogs fed the 1.72% Ca diet than those fed the 0.55% and 2.53% diets (P < 0.05). Bullfrogs fed the 1.72% Ca diet had higher activity of superoxide dismutase in the serum than those fed the 0.55% and 2.53% diets (P < 0.05). Compared to the control group, contents of 1,25 dihydroxyvitamin D3 and parathyroid hormone in the serum as well as vitamin D receptor and sodium-calcium exchanger genes expression in the kidney were significantly decreased in bullfrogs fed the 1.72%, 2.02% and 2.53% Ca diets (P < 0.05). Compared to the control group, intestinal sodium-calcium exchanger gene expression was significantly decreased in bullfrogs fed the 1.72% and 2.02% Ca diets (P < 0.05). Based on second order polynomial analysis of weight gain rate, dietary Ca requirement of bullfrog was 1.89%.
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The calcium-sensing receptor (CaSR) is highly expressed in the kidney especially on the apical surface and basolateral membrane of the DCT and HL (Graca et al., 2016) and has a pivotal role in the kidney by regulating calcium reabsorption and adjust extracellular calcium concentrations (Vezzoli et al., 2009). Furthermore, elevated extracellular calcium levels activate the CaSR of the DCT which stimulate (gastrin and calcitonin) and dampen secretion (insulin and parathyroid hormone) (Riccardi, 1999). Moreover, CaSR is expressed in osteoblasts, mature osteoblast precursors (Dvorak et al., 2004), and involved in the enhancement of bone formation and mineralization (Chattopadhyay et al., 2004).
Osteoblast activating peptide (OBAP) is a newly discovered peptide detected in the rat stomach, which has a major role in osteogenesis. Recently, we revealed its localization in the parietal cells of the rat stomach. There have been no data regarding OBAP expression in the kidney, despite its role in calcium reabsorption in renal tubules. The current study aimed to inspect the expression of OBAP in the kidney of twelve 10-week-old male C3H/HeNJc1 mice using immunohistochemistry, and immunoelectron microscopic localization. The immunohistochemical investigation revealed an OBAP positive reaction mainly in the medulla, which was stronger than the cortex of the kidney and was concentrated in the distal convoluted tubules (DCT), connecting tubules (CT), and the thick limbs of the loop of Henle (HL). Moreover, we clarified that the OBAP was co-distributed with ghrelin and calbindin (markers of the DCT). Interestingly, immunoelectron microscopy demonstrated that OBAP was concentrated in the mitochondrial inner membrane of the DCT and CT. Based on these results, it was concluded that the mitochondria of the DCT, CT, and HL of the mice kidney generate OBAP. Furthermore, our results suggest that OBAP might have a role in the regulation of calcium reabsorption by the renal tubule; however, further investigations are required to clarify this potential role.
The Zn <sup>2+</sup> -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl <sup>−</sup> absorption, via basolateral KCC1, and reduces fluid loss
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Interestingly, the Ca2 + sensing Gq-coupled receptor, CaR, was already linked to reduction of fluid secretion [76] triggered by CTx. We and others have shown that ZnR/GPR39 activity is distinct from the CaR mediated activity, and moreover that CaR is not activated by Zn2 + [19,20,77–79]. Moreover, CaR dependent regulation of Cl− transport was clearly mediated by a bumetanide-sensitive NKCC while ZnR/GPR39 upregulated a KCC-dependent pathway.
Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn²⁺ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn²⁺ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn²⁺ and ZnR/GPR39 are both required for a beneficial effect of Zn²⁺ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl⁻ transport, a critical factor in diarrhea, by upregulating K⁺/Cl⁻ cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl⁻ absorption pathway. Finally, inhibition of KCC-dependent Cl⁻ transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn²⁺ acting via ZnR/GPR39 has a direct role in controlling Cl⁻ absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.
Extracellular calcium-sensing receptors in fishes
2008, Comparative Biochemistry and Physiology - A Molecular and Integrative Physiology
The extracellular calcium-sensing receptor (CaSR) in fishes, like the CaSRs of tetrapod vertebrates, is a dimeric seven transmembrane, G protein-coupled receptor. The receptor is expressed on the plasma membranes of a variety of tissues and cells where it functions as a sensor of extracellular calcium concentration ([Ca²⁺]_o) in the physiological range. In the context of systemic calcium homeostasis, CaSR expressed in endocrine tissues that secrete calciotropic and other hormones (pituitary gland and corpuscles of Stannius) may play a central role in global integrative signaling, whereas receptor expressed in ion-transporting tissues (kidney, intestine, gills, and elasmobranch rectal gland) may have local direct effects on monovalent and divalent ion transport that are independent of endocrine signaling. In fishes, specifically, CaSR expression at the body surface (at the gills and olfactory tissues, for example) may permit direct sensing of environmental Ca²⁺ and Mg²⁺ concentrations, especially in the marine environment. Additionally, CaSRs may have other widespread and diverse roles in extracellular Ca²⁺ sensing related both to organismal calcium homeostasis and to intercellular Ca²⁺ signaling. As a consequence of the broad spectrum of recognized ligands, including polyvalent cations and amino acids, and of binding site shielding by monovalent cations, additional receptor functionalities related to salinity and nutrient detection are proposed for CaSRs. CaSR expression in the gastrointestinal tract may be multifunctional as a sensor for polyvalent cations and amino acids. Structural and phylogenetic analyses reveal strongly conserved features among CaSRs, and suggest that calcium sensing by mammalian parathyroid gland-type CaSR proteins may be restricted to chordates. Comparative functional and genomic studies that include piscine CaSRs can be useful model systems for testing existing hypotheses regarding receptor function, and will shed light on the evolutionary developmental history of calcium homeostasis in the vertebrates.
Calcium mobilization from fish scales is mediated by parathyroid hormone related protein via the parathyroid hormone type 1 receptor
2005, Regulatory Peptides
The scales of bony fish represent a significant reservoir of calcium but little is known about their contribution, as well as of bone, to calcium balance and how calcium deposition and mobilization are regulated in calcified tissues. In the present study we report the action of parathyroid hormone-related protein (PTHrP) on calcium mobilization from sea bream (Sparus auratus) scales in an in vitro bioassay. Ligand binding studies of piscine ¹²⁵I-(1–35^tyr)PTHrP to the membrane fraction of isolated sea bream scales revealed the existence of a single PTH receptor (PTHR) type. RT-PCR of fish scale cDNA using specific primers for two receptor types found in teleosts, PTH1R, and PTH3R, showed expression only of PTH1R. The signalling mechanisms mediating binding of the N-terminal amino acid region of PTHrP were investigated. A synthetic peptide (10^− 8 M) based on the N-terminal 1–34 amino acid residues of Fugu rubripes PTHrP strongly stimulated cAMP synthesis and [³H]myo-inositol incorporation in sea bream scales. However, peptides (10^− 8 M) with N-terminal deletions, such as (2–34), (3–34) and (7–34)PTHrP, were defective in stimulating cAMP production but stimulated [³H]myo-inositol incorporation. (1–34)PTHrP induced significant osteoclastic activity in scale tissue as indicated by its stimulation of tartrate-resistant acid phosphatase. In contrast, (7–34)PTHrP failed to stimulate the activity of this enzyme. This activity could also be abolished by the adenylyl cyclase inhibitor SQ-22536, but not by the phospholipase C inhibitor U-73122.
The results of the study indicate that one mechanism through which N-terminal (1–34)PTHrP stimulates osteoclastic activity of sea bream scales, is through PTH1R and via the cAMP/AC intracellular signalling pathway. It appears, therefore, that fish scales can act as calcium stores and that (1–34)PTHrP regulates calcium mobilization from them; it remains to be established if this mechanism contributes to calcium homeostasis in vivo.
The extracellular zinc-sensing receptor mediates intercellular communication by inducing ATP release
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Our previous results have unambiguously demonstrated that ZnR is distinct from the calcium-sensing receptor (CaR) [15]. Yet because the latter receptor and other members of this family harbor multiple allosteric binding sites, we sought to determine whether Cae2+ modulates ZnR activity [19]. Dose–response analysis for Zn2+ was performed in the absence and presence of extracellular Ca2+ (Fig. 3) and the data were fitted to the Michaelis–Menten equation.
Taste and salivary secretion disorders have been linked to zinc deficiency, indeed zinc is found in secretory granules in the salivary gland. The signaling role for the zinc release in this tissue, however, is poorly understood. Here, we address the signaling pathways and physiological role of the zinc-sensing receptor, ZnR, in the ductal salivary gland cell line, HSY. Exposure of these cells to zinc triggered intracellular Ca²⁺ release from thapsigargin-sensitive stores. The Gαq inhibitor, YM-254890 (1 μM), eliminated the Zn²⁺-dependent Ca²⁺ response, demonstrating that ZnR is a Gαq-coupled receptor. Dose–response curves yielded an apparent K_0.5 of 36 μM and a Hill coefficient of 7 in the absence of extracellular Ca²⁺, and K_0.5 of 55 μM with a Hill coefficient of 3 in its presence. This indicates that although Zn²⁺ is essential for ZnR activation, Ca²⁺ may affect the receptor co-operativity. The homologous desensitization pattern of ZnR was characterized by pre-exposure of cells to Zn²⁺ at concentrations found to activate the receptor. Re-exposure of cells to Zn²⁺ elicited an attenuated Zn²⁺-dependent Ca²⁺ response for at least 3 h, indicating that the ZnR is strongly desensitized by Zn²⁺. Finally, we studied the paracrine affects of ZnR using a co-culture consisting of the HSY cells and vascular smooth muscle cells (VSMCs). While no Zn²⁺-dependent Ca²⁺ release was observed in VSMC alone, application of Zn²⁺ to the co-culture induced a Ca²⁺ rise in both HSY cells and VSMC. This Ca²⁺ rise was inhibited by the ATP scavenger, apyrase. Taken together, our results demonstrate that ZnR activity is monitored in salivary cells and is modulated by extracellular Ca²⁺. We further show that ZnR enhances secretion of ATP, thereby linking zinc to key signaling pathways involved in modification of salivary secretions by the ductal cells.

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TOPICAL REVIEWCell surface, Ca2+(cation)-sensing receptor(s): one or many?

Abstract

TEM

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Comm

J Biol Chem

Cell

Neuron

Neuron

J Biol Chem

Genomics

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Biochem Biophys Res Comm

Am J Clin Nutr

J Biol Chem

Biochem Biophys Res Comm

Brain Res

Biochem Biophys Res Commun

Biochem Biophys Res Comm

Gastroenterology

J Biol Chem

Am J Obstet Gynecol

Biochem Biophys Res Commun

Sequence and expression of a metabotropic glutamate receptor

Nature

Expression cloning of GABA (B) receptors uncovers similarity to metabotropic glutamate receptors

Nature

Putative pheromone receptors related to the Ca2+-sensing receptor in Fugu

Proc Natl Acad Sci USA

Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid

Nature

Extracellular Ca2+-sensing, regulation of parathyroid cell function and role of Ca2+and other ions as extracellular (first) messengers

Physiol Rev

TOPICAL REVIEW
Cell surface, Ca²⁺(cation)-sensing receptor(s): one or many?

Putative pheromone receptors related to the Ca²⁺-sensing receptor in Fugu

Cloning and characterization of an extracellular Ca²⁺-sensing receptor from bovine parathyroid

Extracellular Ca²⁺-sensing, regulation of parathyroid cell function and role of Ca²⁺and other ions as extracellular (first) messengers