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ORIGINAL ARTICLE
Year : 2013  |  Volume : 26  |  Issue : 2  |  Page : 105-107

Calcium-sensing receptors, biology, and clinical significance: a systemic review


Internal Medicine Department, Faculty of Medicine, Menoufia University, Shibin Al Kawm, Egypt

Date of Submission05-Apr-2013
Date of Acceptance06-Jun-2013
Date of Web Publication31-Jan-2014

Correspondence Address:
Karam S Mostafa
MBBCh, Internal Medicine Department, Faculty of Medicine, Menoufia University, Estanha-Elbagour, Shibin Al Kawm
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.126134

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  Abstract 

This is a study of calcium-sensing receptors (CaSR), biology, and clinical significance. The CaSR plays an essential role in the regulation of extracellular calcium (Ca 2+ ) homeostasis. CaSR is expressed in all tissues related to this control (parathyroid glands, thyroid C cells, kidneys, intestine, and bones) and also in tissues with apparently no role in the maintenance of extracellular Ca 2+ levels, such as the brain, skin, and pancreas. CaSR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaSR mutations: Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaSR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaSR-activating mutations. Study of CaSR functions aided the development of drugs that modify their functions either by stimulation (calcimimetic drugs) or by inhibition (calcilytic drugs). CaSR plays a major role in the maintenance of a physiological serum Ca 2+ concentration. There are a number of inherited and acquired conditions in which the level of expression and/or function of the CaSR are altered. Also, there are drugs that modify the function of calcium-sensing receptors (CaSR-based therapeutics).

Keywords: Calcilytic, calcimimetic, calcium homeostasis, calcium-sensing receptor, CaSR mutations


How to cite this article:
Galal AZ, Shoeb SA, Tawfeek AR, Mostafa KS. Calcium-sensing receptors, biology, and clinical significance: a systemic review. Menoufia Med J 2013;26:105-7

How to cite this URL:
Galal AZ, Shoeb SA, Tawfeek AR, Mostafa KS. Calcium-sensing receptors, biology, and clinical significance: a systemic review. Menoufia Med J [serial online] 2013 [cited 2020 Feb 23];26:105-7. Available from: http://www.mmj.eg.net/text.asp?2013/26/2/105/126134


  Introduction Top


The calcium-sensing receptor (CaSR) is important in close monitoring of the blood Ca 2+ level. When it detects any change in Ca +2 from its normal level, the CaSR directly or indirectly modulates various homeostatic tissues to normalize Ca +2 [1] . Key CaSR-expressing, homeostatic tissues include the parathyroid hormone (PTH)-secreting parathyroid glands, calcitonin (CT)-secreting thyroidal C cells, intestines, bone, and kidney. The latter three determine how much Ca 2+ moves into or out of the body (intestine and kidney, respectively) or how Ca 2+ moves between the extracellular fluids and bone. These Ca 2+ fluxes are regulated by PTH and CT as well as by 1,25-dihydroxyvitamin D3 [1,25(OH)2D 3] , whose renal synthesis is homeostatically regulated [2] .

Structure and function of CaSR

The extracellular domain of the human CaSR comprises 612 amino acids, where most of the activating and inactivating mutations are described, and is followed by a 250 amino acid domain of seven transmembrane domain and finally by a carboxy terminal (C) tail of 200 amino acids [3] .

The role of CaSR in parathyroid glands: the CaSR controls three important aspects of parathyroid function relevant to the kidney: (a) PTH secretion, (b) PTH synthesis, and (c) parathyroid cellular proliferation. Inactivating mutations of the CaSR gene result in markedly elevated PTH levels and parathyroid hyperplasia despite their marked hypercalcemia. Therefore, the CaSR tonically inhibits both PTH secretion and parathyroid cellular proliferation. The CaSR also controls expression of the PTH gene by a posttranscriptional mechanism [2] .

The role of CaSR and the kidney: the CASR is present in the subapical region of proximal tubular cells, where it is involved in the regulation of PTH-mediated phosphate excretion. Thus, CaSR exerts a tight control on circulating 1,25(OH)2D3 both at the level of its synthesis (in the proximal tubule) and in modulating its effects (specifically, on Ca 2+ reabsorption by the distal tubule) [4] . About 20-25% of the filtered calcium is reabsorbed in the loop of Henle, largely by the cortical (CTAL) and, to a lesser extent, by the medullary (MTAL) thick ascending limb, through both transcellular and paracellular routes. The CaSR is expressed at the basolateral side of TAL cells, where it directly controls both paracellular and transcellular NaCl and divalent cation transport Ca 2+ (or Mg 2+ ) [5] . CaSR in the distal convoluted tubule (DCT) and connecting tubule (CNT) account for 15% of total Ca 2+ reabsorbed by the kidney and Ca 2+ reabsorption in these nephron segments is inversely related to Na + transport. In DCT and CNT, the transepithelial potential difference is against Ca 2+ reabsorption and the paracellular permeability of Ca 2+ ions is very low. Ca 2+ reabsorption is an active, transcellular process that is regulated by PTH and 1,25(OH)2D3 [6] . The CaSR is expressed in collecting ducts and the activation of CaSR induces urine acidification and a reduction in water reabsorption, thereby allowing for urinary Ca 2+ excretion to proceed in the presence of a reduced risk of kidney stone formation. The effects of CaSR activation on urinary-concentrating ability are even more obvious in the inner medullary collecting duct (IMCD). It is well established that hypercalcemia can lead to hypercalciuria, urinary-concentrating defects, and polyuria, and the IMCD is the site that controls the final production of urine [7,8] . Also, the CaSR is expressed in juxtaglomerular apparatus (JG) cells and activation of the receptor decreases renin secretion by suppressing the activity of the Ca 2+ -inhibitable type V adenylate cyclase (AC-V) [9] .

The CaSR play various roles in the gastrointestinal tract. In the stomach, it stimulates gastric acid and gastrin secretion; in the small intestine, it enhances cholecystokinin release, which stimulates pancreatic enzyme secretion and gallbladder contraction. In the colon, it enhances differentiation of colonocytes (thereby reducing colonic neoplasia in some settings) and inhibits fluid and electrolyte secretion, which could potentially serve as a treatment for diarrheal disease [10] . The presence and roles of CaSR in bone cells have been controversial. However, recent evidence strongly supports the receptor's expression in osteoclast precursors and mature osteoclasts as well as in preosteoblasts and osteoblasts. Whereas the CaSR appears to play a permissive role in osteoclastogenesis, high Ca 2+ concentrations (5-20 mmol/l) directly inhibit osteoclast activity and stimulate their apoptosis [11] .

Inherited and acquired disorders impacting function of CaSR

Familial hypocalciuric hypercalcemia (FHH) is a benign, autosomal dominant form of hypercalcemia with characteristic abnormalities in the regulation of parathyroid and renal function by Ca 2+ . FHH patients typically show asymptomatic, mild-to-moderate, PTH-dependent hypercalcemia of about 11 mg/dl (total calcium) and an inappropriately normal or even overtly low urinary Ca 2+ excretion despite their hypercalcemia. Serum Mg 2+ levels are often high-normal or mildly elevated, suggesting that the CaSR contributes to 'setting' Mg 2+ as well as Ca 2+ . Serum PTH is generally normal, although 15-20% of patients have elevated levels. Serum phosphate is usually normal or mildly decreased, and serum 1,25(OH)2D3 and bone mineral density (BMD) are normal, although bone turnover markers may be mildly elevated. There is a considerable reduction in renal Ca 2+ clearance in FHH, and the ratio of Ca 2+ clearance to creatinine clearance, the most useful parameter of renal Ca 2+ handling in this condition, is less than 0.01 in 80% of patients. About 80% of patients with primary hyperparathyrodism (PHPT), in contrast, have values greater than 0.01 and commonly greater than 0.02. Mg 2+ clearance is reduced but to a lesser degree (30%) in FHH [12] .

Neonatal severe primary hyperparathyroidism (NSHPT) typically presents in the first 6 months of life, often in the immediate neonatal period, with severe, symptomatic, PTH-dependent hypercalcemia and the bony changes of severe hyperparathyroidism. Infants with NSHPT can also manifest polyuria, dehydration, hypotonia, and failure to thrive. The bone disease can produce multiple fractures of long bones, ribs (sometimes impairing respiration), and other sites. Total serum Ca 2+ levels range from moderately elevated (e.g. 12-14 mg/dl) to as high as 25-30 mg/dl. PTH levels are frequently 10-fold or more above the upper normal limit. Early diagnosis is critical, as untreated NSHPT can have a fatal outcome or severe impairment of subsequent mental, skeletal, and somatic growth without parathyroidectomy to alleviate the hyperparathyroidism and hypercalcemia [13] .

Autosomal dominant hypoparathyroidism (ADH) patients with activating CaSR mutations have an often asymptomatic, autosomal dominant form of hypocalcemia/hypoparathyroidism. Some, however, manifest neuromuscular irritability, basal ganglia calcification, and seizures, complications observed in hypoparathyroidism of other causes [14] .

Several patients have been reported with activating CaSR mutations and features of Bartter syndrome (a syndrome referred to as Bartter syndrome, type V). In addition to the typical features of ADH, these patients also showed hypokalemia with renal K + wasting, hyperreninemia, and hyperaldosteronemia [15] .

CaSR-based therapeutics

The development of allosteric CaSR activators (calcimimetics) and antagonists (calcilytics) has enabled novel, CaSR-based therapy of disorders of calcium homeostasis. Cinacalcet hydrochloride was approved in 2004 by the FDA for the treatment of severe secondary hyperparathyroidism(SHPT) in stage 5 kidney disease as well as parathyroid cancer. Studies in experimental animals have suggested that administration of a calcimimetic in uremic animals reduces some of the long-term complications of this condition, including progression of renal impairment, atherosclerosis, and, in combination with vitamin D treatment, mortality. Studies are currently in progress in humans assessing the efficacy of the drug in decreasing cardiovascular disease and mortality [16] . The drug also effectively lowers serum Ca 2+ concentration in mild PHPT. The drug has been utilized in several other, 'off-label' uses. Others may represent significant advances that will improve patient care in certain clinical settings. The drug has been used to control hypercalcemia/hyperparathyroidism in patients with renal insufficiency, other than in stage 5. One application is the use of the drug to treat hyperparathyroidism in CKD before dialysis. Although cinacalcet lowers PTH in this setting, it also modestly lowers serum Ca 2+ and increases serum phosphate [17] . The utility of the drug in this setting is currently unclear. A potentially valuable application is in the treatment of PTH-dependent hypercalcemia following renal transplantation. Cinacalcet restores normocalcemia in about 80% of such patients, with few adverse effects, except for occasional hypercalciuria and mild, generally reversible, reductions in graft function in some patients [18] .

The CaSR antagonists, so-called calcilytics, directly increase PTH secretion and indirectly increase plasma Ca 2+ concentrations and urinary phosphate excretion. Therefore, because of the anabolic effects of PTH on bone, calcilytics have been suggested to have promise in the prevention and treatment of osteoporosis [8],[19] .


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001; 81 :239-297.  Back to cited text no. 1
    
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4.Maiti A, Beckman MJ. Extracellular calcium is a direct effecter of VDR levels in proximal tubule epithelial cells that counter-balances effects of PTH on renal vitamin D metabolism. J Steroid Biochem Mol Biol 2007; 103 :504-508.  Back to cited text no. 4
    
5.Daniela R, Brown EM. Physiology and pathophysiology of the CaSR in the kidney. Am J Physiol Renal Physiol 2010; 298 :485-499.  Back to cited text no. 5
    
6.Topala CN, Schoeber JP, Searchfield LE, Riccardi D, Hall AE, et al. Activation of the CaSR stimulates the activity of the epithelial Ca 2+ channel. Cell Calcium 2009; 45 :331-339.  Back to cited text no. 6
    
7.Renkema KY, Velic A, Dijkman HB, Spiegel AM, Downs RW, Nowik M, et al. The CaSR promotes urinary acidification to prevent nephrolithiasis. J Am Soc Nephrol 2009; 20 :1705-1713.  Back to cited text no. 7
    
8.Widler L. Calcilytics, antagonists of the CaSR for the treatment of osteoporosis. Future Med Chem 2011; 3 :535-547.  Back to cited text no. 8
    
9.Capisano MC, Liao TD, Ortiz PA, Janicic N, Salisbury SR, Rizzo M, et al. Calcium-dependent phosphodiesterase inhibits renin release from isolated juxtaglomerular cells. Am J Physiol Regul Integr Comp Physiol 2009; 297 :1469-1476.  Back to cited text no. 9
    
10.Behar J, Hitchings M, Smyth RD, Silverberg SJ, Spiegel AM, Stauffer UG, et al. Calcium stimulation of gastrin and gastric acid secretion: effect of small doses of calcium carbonate. Gut 2007; 18 :442-448.  Back to cited text no. 10
    
11.Caudarella R, Vescini F, Buffa A, Heickendorff L, Brixen K, Berger N, et al. Role of CaSR in bone biology. J Endocrinol Invest 2011; 34 :130-137.  Back to cited text no. 11
    
12.Marx SJ, Fraser D, Rapoport A. FHH. Mild expression of the gene in heterozygotes and severe expression in homozygotes. Am J Med 2009; 78 :15-22.  Back to cited text no. 12
    
13.Pearce SH, Trump D, Wooding C, Bollman S, Kumar R, Hughes IA, et al. CaSR mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 2005; 96 :2683-2692.  Back to cited text no. 13
    
14.Lienhardt A, Garabedian M, Bai M, Eisenberger U, Frey FJ, Rigaud M, et al. A large homozygous or heterozygous in-frame deletion within the CaSR carboxylterminal cytoplasmic tail that causes ADH. J Clin Endocrinol Metab 2000; 85 :1695-1702.  Back to cited text no. 14
    
15.Huang C, Hulin P, Houillier P, Harbouche L, Monge M, Sugatani J, et al. Functional characterization of a CaSR mutation in severe ADH a with a Bartter-like syndrome. J Am Soc Nephrol 2002; 13 :2259-2266.  Back to cited text no. 15
    
16.Smajilovic S, Yano S, Jabbari R, Garvin JL, Harding P, Bittiger H, et al. The CaSR and calcimimetics in blood pressure modulation. Br J Pharmacol 2012; 164 :884-893.  Back to cited text no. 16
    
17.Sprague SM, Evenepoel P, Curzi MP, Williamson C, Kifor O, Arnold AL, et al. Simultaneous control of PTH and Ca x P is sustained over three years of treatment with cinacalcet HCl. Clin J Am Soc Nephrol 2009; 4 :1465-1476.  Back to cited text no. 17
    
18.Cozzolino M, Mazzaferro S, Messa P. New insights into the role of CaSR activation. J Nephrol 2012; 18 :38-41.  Back to cited text no. 18
    
19.Kessler A, Faure H, Petrel C, Durand D, Kamar N, Lanske B, et al. Development of 4-chlorophenylcarboxamide (calhex 231) as a new CaSR ligand demonstrating potent calcilytic activity. J Med Chem 2006; 49 :5119-5128.  Back to cited text no. 19
    




 

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