Calcium-sensing receptor

CASR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5FBH, 5FBK, 7DTT, 7SIN, 7DD6, 7DTW
Identifiers
Aliases	CASR , CAR, EIG8, FHH, FIH, GPRC2A, HHC, HHC1, HYPOC1, NSHPT, PCAR1, calcium sensing receptor, hCasR, Calcium-sensing receptor+CaSR
External IDs	OMIM: 601199; MGI: 1351351; HomoloGene: 332; GeneCards: CASR; OMA:CASR - orthologs
Gene location (Human) Chr. Chromosome 3 (human) [1] Band 3q13.33-q21.1 Start 122,183,668 bp [1] End 122,291,629 bp [1]
Gene location (Mouse) Chr. Chromosome 16 (mouse) [2] Band 16 B3|16 25.57 cM Start 36,314,058 bp [2] End 36,382,503 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans body of pancreas human kidney buccal mucosa cell pancreatic ductal cell gallbladder renal medulla kidney tubule duodenum liver Top expressed in muscle of thigh sternocleidomastoid muscle right kidney outer renal medulla human kidney distal tubule triceps brachii muscle islet of Langerhans quadriceps femoris muscle vastus lateralis muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding signal transducer activity phosphatidylinositol phospholipase C activity G protein-coupled receptor activity amino acid binding protein homodimerization activity metal ion binding magnesium ion binding calcium ion binding polyamine binding integrin binding protein kinase binding transmembrane transporter binding signaling receptor activity Cellular component integral component of membrane plasma membrane membrane integral component of plasma membrane nucleus cytoplasm cell surface basolateral plasma membrane apical plasma membrane axon neuron projection neuronal cell body axon terminus Biological process chemosensory behavior calcium ion import anatomical structure morphogenesis signal transduction detection of calcium ion G protein-coupled receptor signaling pathway ossification response to ischemia calcium ion transport cellular calcium ion homeostasis apoptotic process adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway phospholipase C-activating G protein-coupled receptor signaling pathway JNK cascade positive regulation of cell population proliferation response to metal ion positive regulation of gene expression response to organic cyclic compound positive regulation of insulin secretion positive regulation of ATP-dependent activity cellular response to hepatocyte growth factor stimulus vasodilation positive regulation of vasoconstriction branching morphogenesis of an epithelial tube positive regulation of positive chemotaxis response to calcium ion regulation of calcium ion transport fat pad development cellular response to vitamin D cellular response to glucose stimulus cellular response to low-density lipoprotein particle stimulus cellular response to hypoxia response to fibroblast growth factor positive regulation of calcium ion import cellular response to peptide bile acid secretion chloride transmembrane transport positive regulation of ERK1 and ERK2 cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 846 12374 Ensembl ENSG00000036828 ENSMUSG00000051980 UniProt P41180 Q9QY96 RefSeq (mRNA) NM_000388 NM_001178065 NM_013803 RefSeq (protein) NP_000379 NP_001171536 NP_038831 Location (UCSC) Chr 3: 122.18 – 122.29 Mb Chr 16: 36.31 – 36.38 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain. ^{[5] [6]} In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). ^[7] In the kidney it has an inhibitory effect on the reabsorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated. ^[8]

Since the initial review of CaSR, ^[9] there has been in-depth analysis of its role related to parathyroid disease and other roles related to tissues and organs in the body. 1993, Brown et al. ^[10] isolated a clone named BoPCaR (bovine parathyroid calcium receptor) which replicated the effect when introduced to polyvalent cations. Because of this, the ability to clone full-length CaSRs from mammals were performed. ^[11]

Structure

Each protomer of the receptor has a large, N-terminal extracellular domain that linked to create VFT (Venus flytrap) domain. The receptor has a CR (cysteine-rich) domain that links the VFT to the 7 transmembrane domains of the receptor. The 7 transmembrane domain is followed by a long cytoplasmatic tail. The tail has no structure, but still, it has an important role in trafficking and phosphorylation. ^[12]

The CaSR is a homodimer receptor. The signal transmission occurs only when the agonist binds to the homodimer of the CaSR. Binding of a single protomer will not lead to signal transmission. In vitro experiments showed that the receptor can form a heterodimer with mGlu1/5 or with GABAB receptor. The heterodimerization may facilitate the varied functional roles of the CaSR in different tissues, particularly in the brain.

The CryoEM structures of CasR homodimer was recently solved

Extracellular domain

The VFT extends outside the cell and is composed of two lobe subdomains. Each lobe forms part of the ligand binding cleft.

In contrast to the conservative structure of other class C GPCR receptors, the CaSR cleft is an allosteric or co-agonist binding site, with the cations (Ca²⁺) binding elsewhere.

The inactive state of the receptor has two extracellular domains, oriented in an open conformation with an empty intradomain part. When the receptor is activated, the two lobes interact with each other and creates a rotation of the interdomain cleft. ^[13]

Cation binding sites

The cation binding sites varied in their location and in the number of repetitive appearances. ^[13]

The receptor has four Calcium binding sites that have a role in the stabilization ^[13] of the extracellular domain (ECD) and in the activation of the receptor. The stabilization maintains the receptor in its active conformation.

Calcium cations bind to the first Calcium binding site in the inactive conformation. In the second binding site, Calcium cations are bound to both the active and inactive structures. In the third binding Site, the binding of the calcium facilitates the closure of lobe 1 and 2. This closure permits the interaction between the two lobes. The fourth binding site is located on lobe 2 in a place close to the CR domain. The agonist binding to the fourth binding site leads formation of homodimer interface bridge. This bridge between lobe 2 domain of subunit 1 and the CR domain of subunit 2, stabilize the open conformation.

The order of Calcium binding affinity to four of the bindings sites is as follows: 1 = 2 > 3 > 4. The lower affinity of Calcium to site 4 indicates that the receptor is activated only when the calcium concentration is elevated above the required concentration. That behavior makes the binding of calcium at site 4 to hold a major role in stabilization.

The CaSR also has binding sites for Magnesium and Gadolinium.

Anion binding sites

There are four anion binding sites in the ECD. Sites 1-3 are occupied in the inactive structure, whereas in the active structure only sites 2 and 4 are occupied.

7-Transmembrane domain

Based on a similarity of CaSR to mGlu5, it is believed that in the inactivated form of the receptor, the VFT domain disrupts the interface between the 7TM domains, and the activation of the receptor force a reorientation of the 7TM domains. ^[14]

Signal transduction

The inactivated form of the receptor has an open conformation. upon binding of the fourth binding site, the structure of the receptor changes to a close conformation. The change in the structure conformation leads to inhibition of PTH release.

On the intracellular side, initiates the phospholipase C pathway, ^{[15] [16]} presumably through a G_qα type of G protein, which ultimately increases intracellular concentration of calcium, which inhibits vesicle fusion and exocytosis of parathyroid hormone. It also inhibits (not stimulates, as some ^[17] sources state) the cAMP dependent pathway. ^[16]

Ligands

Agonists

• Calcium
• Spermine ^[18]
• Neomycin ^[19]
• Vitamin D

Positive allosteric modulators

• Gamma-Glutamyl peptides
• L- amino acids
• Cinacalcet
• Evocalcet
• NPS R-568
• NPS R-467
• Etelcalcetide
• Calhex 231

Antagonists

• Calcilytics
• Phosphate ^[20]

Negative allosteric modulators

• NPS 2143
• Ronacaleret
• Calhex 231

It is unknown whether Ca²⁺ alone can activate the receptor, but L-amino acids and g-Glutamyl peptides are shown to act as co-activator of the receptor. Those molecules intensify the intracellular responses evoked by Calcium cation. ^[21]

Pathology

Mutations that inactivate a CaSR gene cause familial hypocalciuric hypercalcemia (FHH) (also known as familial benign hypercalcemia because it is generally asymptomatic and does not require treatment), ^[22] when present in heterozygotes. Patients who are homozygous for CaSR inactivating mutations have more severe hypercalcemia. ^[23] Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia ^[24] or Type 5 Bartter syndrome. An alternatively spliced transcript variant encoding 1088 aa has been found for this gene, but its full-length nature has not been defined. ^[25]

Role in Chronic kidney disease

In CKD, the dysregulation of CaSR leads to a secondary hyperparathyroidism linked with osteoporosis, which considered as one of the main complications.

Patients suffers from secondary hyperparathyroidism require to make changes in their diet in order to balance the disease. ^[26] The diet recommendation includes restriction of Calcium, phosphate, and protein intake. Those nutrients are abundance in our diet and because of that, avoiding foods that contains those nutrients may limit our dietary options and can lead to other nutrients deficiencies.

Therapeutic application

The drugs cinacalcet and etelcalcetide are allosteric modifiers of the calcium-sensing receptor. ^[27] They are classified as a calcimimetics, binding to the calcium-sensing receptor and decreasing parathyroid hormone release.

Calcilytic drugs, which block CaSR, produce increased bone density in animal studies and have been researched for the treatment of osteoporosis. Unfortunately clinical trial results in humans have proved disappointing, with sustained changes in bone density not observed despite the drug being well tolerated. ^{[28] [29]} More recent research has shown the CaSR receptor to be involved in numerous other conditions including Alzheimer's disease, asthma and some forms of cancer, ^{[30] [31] [32] [33]} and calcilytic drugs are being researched as potential treatments for these. Recently it has been shown that biomimetic bone like apatite inhibits formation of bone through endochondral ossification pathway via hyperstimulation of extracellular calcium sensing receptor. ^[34]

Transactivation across the dimer can result in unique pharmacology for CaSR allosteric modulators. For example, Calhex 231, which shows a positive allosteric activity when bound to the allosteric site in just one protomer. In contrast, it shows a negative allosteric activity when occupying both the allosteric sites of the dimer. ^[18]

Interactions

Calcium-sensing receptor has been shown to interact with filamin. ^{[35] [36]}

Role in sensory evaluation of food

Kokumi was discovered in Japan, 1989. It is defined as a sensation that enhances existing flavors and creates feelings of roundness, complexity, and richness in the mouth. The kokumi is present in different foods such as fish sauce, soybean, garlic, beans, etc. ^[37] The Kokumi substances are Gamma-glutamyl peptides.

CaSR is known to be expressed in the parathyroid gland and kidneys, but recent experiments showed that the receptor is also expressed in the alimentary canal (known as the digestive tract) and the near the taste buds on the back of the tongue. ^[38]

Gamma-glutamyl peptides are allosteric modulators of the CaSR, and the binding of those peptides to the CaSR on the tongue is what mediates the Kokumi sensation in the mouth.

In the mouth, unlike in other tissues, the influx of the extracellular Calcium does not affect the receptor activity. Instead, the activation of the CaSR is by the binding of the Gamma glutamine peptides.

Taste signal involves a release of intracellular calcium as respond to the molecule binding to the taste receptor, leads to secretion of neurotransmitter and taste perception. The simultaneous binding of gamma glutamine peptides to the CaSR increases the level of the intracellular calcium, and that intensify the taste perception. ^{[38] [39] [37]}

References

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11. Aida K, Koishi S, Tawata M, Onaya T (September 1995). "Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney". Biochemical and Biophysical Research Communications. 214 (2): 524–529. doi:10.1006/bbrc.1995.2318. PMID   7677761.
12. Leach K, Hannan FM, Josephs TM, Keller AN, Møller TC, Ward DT, et al. (July 2020). "International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function". Pharmacological Reviews. 72 (3): 558–604. doi:10.1124/pr.119.018531. PMC   7116503 . PMID   32467152.
13. Geng Y, Mosyak L, Kurinov I, Zuo H, Sturchler E, Cheng TC, et al. (July 2016). Isacoff EY (ed.). "Structural mechanism of ligand activation in human calcium-sensing receptor". eLife. 5: e13662. doi: 10.7554/eLife.13662 . PMC   4977154 . PMID   27434672.
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17. Costanzo LS (2007). BRS Physiology (Board Review Series) . Lippincott Williams & Wilkins. pp.  260. ISBN   978-0-7817-7311-9.
18. Gregory KJ, Kufareva I, Keller AN, Khajehali E, Mun HC, Goolam MA, et al. (November 2018). "Dual Action Calcium-Sensing Receptor Modulator Unmasks Novel Mode-Switching Mechanism". ACS Pharmacology & Translational Science. 1 (2): 96–109. doi:10.1021/acsptsci.8b00021. PMC   7089027 . PMID   32219206.
19. McLarnon SJ, Riccardi D (July 2002). "Physiological and pharmacological agonists of the extracellular Ca2+-sensing receptor". European Journal of Pharmacology. Ca2+ and Neuronal Pathology. 447 (2–3): 271–278. doi:10.1016/S0014-2999(02)01849-6. PMID   12151018.
20. Centeno PP, Herberger A, Mun HC, Tu C, Nemeth EF, Chang W, et al. (October 2019). "Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion". Nature Communications. 10 (1): 4693. Bibcode:2019NatCo..10.4693C. doi:10.1038/s41467-019-12399-9. PMC   6795806 . PMID   31619668.
21. Zhang C, Zhuo Y, Moniz HA, Wang S, Moremen KW, Prestegard JH, et al. (November 2014). "Direct determination of multiple ligand interactions with the extracellular domain of the calcium-sensing receptor". The Journal of Biological Chemistry. 289 (48): 33529–33542. doi: 10.1074/jbc.m114.604652 . PMC   4246106 . PMID   25305020.
22. Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN (June 2005). "Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia". Human Molecular Genetics. 14 (12): 1679–1690. doi: 10.1093/hmg/ddi176 . PMID   15879434.
23. Egbuna OI, Brown EM (March 2008). "Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations". Best Practice & Research. Clinical Rheumatology. 22 (1): 129–148. doi:10.1016/j.berh.2007.11.006. PMC   2364635 . PMID   18328986.
24. Mancilla EE, De Luca F, Baron J (July 1998). "Activating mutations of the Ca2+-sensing receptor". Molecular Genetics and Metabolism. 64 (3): 198–204. doi:10.1006/mgme.1998.2716. PMID   9719629.
25. "Entrez Gene: CaSR calcium-sensing receptor (hypocalciuric hypercalcemia 1, severe neonatal hyperparathyroidism)".
26. Ikizler TA, Burrowes JD, Byham-Gray LD, Campbell KL, Carrero JJ, Chan W, et al. (September 2020). "KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update". American Journal of Kidney Diseases. 76 (3 Suppl 1): S1–S107. doi: 10.1053/j.ajkd.2020.05.006 . PMID   32829751.
27. Torres PU (July 2006). "Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease". Journal of Renal Nutrition. 16 (3): 253–258. doi:10.1053/j.jrn.2006.04.010. PMID   16825031.
28. Nemeth EF, Shoback D (June 2013). "Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders". Best Practice & Research. Clinical Endocrinology & Metabolism. 27 (3): 373–384. doi:10.1016/j.beem.2013.02.008. PMID   23856266.
29. John MR, Harfst E, Loeffler J, Belleli R, Mason J, Bruin GJ, et al. (July 2014). "AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women". Bone. 64: 204–210. doi:10.1016/j.bone.2014.04.015. PMID   24769332.
30. Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, et al. (November 2014). "Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection". Annals of Clinical and Translational Neurology. 1 (11): 851–866. doi:10.1002/acn3.118. PMC   4265057 . PMID   25540800.
31. Aggarwal A, Prinz-Wohlgenannt M, Tennakoon S, Höbaus J, Boudot C, Mentaverri R, et al. (September 2015). "The calcium-sensing receptor: A promising target for prevention of colorectal cancer". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1853 (9): 2158–2167. doi:10.1016/j.bbamcr.2015.02.011. PMC   4549785 . PMID   25701758.
32. Dal Prà I, Chiarini A, Armato U (February 2015). "Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression?". Neural Regeneration Research. 10 (2): 213–218. doi: 10.4103/1673-5374.152373 . PMC   4392667 . PMID   25883618.
33. Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, P Lowe AP, et al. (April 2015). "Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma". Science Translational Medicine. 7 (284): 284ra60. doi:10.1126/scitranslmed.aaa0282. PMC   4725057 . PMID   25904744.
34. Sarem M, Heizmann M, Barbero A, Martin I, Shastri VP (July 2018). "Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R". Proceedings of the National Academy of Sciences of the United States of America. 115 (27): E6135–E6144. Bibcode:2018PNAS..115E6135S. doi: 10.1073/pnas.1805159115 . PMC   6142224 . PMID   29915064.
35. Hjälm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM (September 2001). "Filamin-A binds to the carboxyl-terminal tail of the calcium-sensing receptor, an interaction that participates in CaR-mediated activation of mitogen-activated protein kinase". The Journal of Biological Chemistry. 276 (37): 34880–34887. doi: 10.1074/jbc.M100784200 . PMID   11390380.
36. Awata H, Huang C, Handlogten ME, Miller RT (September 2001). "Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein". The Journal of Biological Chemistry. 276 (37): 34871–34879. doi: 10.1074/jbc.M100775200 . PMID   11390379.
37. Amino Y, Nakazawa M, Kaneko M, Miyaki T, Miyamura N, Maruyama Y, et al. (2016). "Structure-CaSR-Activity Relation of Kokumi γ-Glutamyl Peptides". Chemical & Pharmaceutical Bulletin. 64 (8): 1181–1189. doi: 10.1248/cpb.c16-00293 . PMID   27477658.
38. Ohsu T, Amino Y, Nagasaki H, Yamanaka T, Takeshita S, Hatanaka T, et al. (January 2010). "Involvement of the calcium-sensing receptor in human taste perception". The Journal of Biological Chemistry. 285 (2): 1016–1022. doi: 10.1074/jbc.m109.029165 . PMC   2801228 . PMID   19892707.
39. Maruyama Y, Yasuda R, Kuroda M, Eto Y (2012-04-12). "Kokumi substances, enhancers of basic tastes, induce responses in calcium-sensing receptor expressing taste cells". PLOS ONE. 7 (4): e34489. Bibcode:2012PLoSO...734489M. doi: 10.1371/journal.pone.0034489 . PMC   3325276 . PMID   22511946.

Further reading

• Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE (October 2000). "Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia". Human Mutation. 16 (4): 281–296. doi: 10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A . PMID   11013439. S2CID   31157004.
• Fukumoto S (March 2002). "[Calcium-sensing receptor in bone cells]". Nihon Rinsho. Japanese Journal of Clinical Medicine. 60 Suppl 3 (Suppl 3): 57–63. PMID   11979955.
• Tfelt-Hansen J, Schwarz P, Brown EM, Chattopadhyay N (May 2003). "The calcium-sensing receptor in human disease". Frontiers in Bioscience. 8 (6): s377–s390. doi: 10.2741/1068 . PMID   12700051.
• Hu J, Spiegel AM (August 2003). "Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function". Trends in Endocrinology and Metabolism. 14 (6): 282–288. doi:10.1016/S1043-2760(03)00104-8. PMID   12890593. S2CID   28822680.
• Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T (September 1995). "Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene". The Journal of Clinical Endocrinology and Metabolism. 80 (9): 2594–2598. doi:10.1210/jcem.80.9.7673400. PMID   7673400.
• Aida K, Koishi S, Tawata M, Onaya T (September 1995). "Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney". Biochemical and Biophysical Research Communications. 214 (2): 524–529. doi:10.1006/bbrc.1995.2318. PMID   7677761.
• Chou YH, Pollak MR, Brandi ML, Toss G, Arnqvist H, Atkinson AB, et al. (May 1995). "Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia". American Journal of Human Genetics. 56 (5): 1075–1079. PMC   1801464 . PMID   7726161.
• Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, et al. (May 1995). "Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs". The Journal of Biological Chemistry. 270 (21): 12919–12925. doi: 10.1074/jbc.270.21.12919 . PMID   7759551.
• Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, et al. (November 1994). "Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation". Nature Genetics. 8 (3): 303–307. doi:10.1038/ng1194-303. PMID   7874174. S2CID   22941518.
• Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, et al. (December 1993). "Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism". Cell. 75 (7): 1297–1303. doi:10.1016/0092-8674(93)90617-Y. PMID   7916660. S2CID   40886966.
• Janicic N, Soliman E, Pausova Z, Seldin MF, Rivière M, Szpirer J, et al. (November 1995). "Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16". Mammalian Genome. 6 (11): 798–801. doi:10.1007/BF00539007. PMID   8597637. S2CID   19835161.
• Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S (February 1996). "Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor". The Journal of Clinical Investigation. 97 (4): 1085–1093. doi:10.1172/JCI118501. PMC   507156 . PMID   8613532.
• Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, et al. (December 1995). "Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism". The Journal of Clinical Investigation. 96 (6): 2683–2692. doi:10.1172/JCI118335. PMC   185975 . PMID   8675635.
• Bai M, Quinn S, Trivedi S, Kifor O, Pearce SH, Pollak MR, et al. (August 1996). "Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor". The Journal of Biological Chemistry. 271 (32): 19537–19545. doi: 10.1074/jbc.271.32.19537 . PMID   8702647.
• Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmerman D, et al. (May 1996). "Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism". Human Molecular Genetics. 5 (5): 601–606. doi:10.1093/hmg/5.5.601. PMID   8733126.
• Freichel M, Zink-Lorenz A, Holloschi A, Hafner M, Flockerzi V, Raue F (September 1996). "Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion". Endocrinology. 137 (9): 3842–3848. doi: 10.1210/endo.137.9.8756555 . PMID   8756555.
• Chattopadhyay N, Ye C, Singh DP, Kifor O, Vassilev PM, Shinohara T, et al. (April 1997). "Expression of extracellular calcium-sensing receptor by human lens epithelial cells". Biochemical and Biophysical Research Communications. 233 (3): 801–805. doi:10.1006/bbrc.1997.6553. PMID   9168937.
• Cole DE, Janicic N, Salisbury SR, Hendy GN (August 1997). "Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene". American Journal of Medical Genetics. 71 (2): 202–210. doi:10.1002/(SICI)1096-8628(19970808)71:2<202::AID-AJMG16>3.0.CO;2-I. PMID   9217223.
• Ward BK, Stuckey BG, Gutteridge DH, Laing NG, Pullan PT, Ratajczak T (1997). "A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with familial hypocalciuric hypercalcemia". Human Mutation. 10 (3): 233–235. doi: 10.1002/(SICI)1098-1004(1997)10:3<233::AID-HUMU9>3.0.CO;2-J . PMID   9298824. S2CID   34382961.
• Quinn SJ, Kifor O, Trivedi S, Diaz R, Vassilev P, Brown E (July 1998). "Sodium and ionic strength sensing by the calcium receptor". The Journal of Biological Chemistry. 273 (31): 19579–19586. doi: 10.1074/jbc.273.31.19579 . PMID   9677383.
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External links

• "Calcium-Sensing Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-10-25.
• CASRdb - Calcium Sensing Receptor Database, McGill University
• Receptors,+Calcium-Sensing at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• CASR+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)