Calcium-sensing receptor explained

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.^{[1] [2]} In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH).^[3] 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.^[4]

Since the initial review of CaSR,^[5] 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.^[6] 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.^[7]

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.^[8]

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 recentlly 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.^[9]

Cation binding sites

The cation binding sites varied in their location and in the number of repetitive appearances.

The receptor has four Calcium binding sites that have a role in the stabilization 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.^[10]

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,^{[11] [12]} 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^[13] sources state) the cAMP dependent pathway.

Ligands

Agonists

• Calcium
• Spermine^[14]
• Neomycin^[15]
• 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^[16]

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.^[17]

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),^[18] when present in heterozygotes. Patients who are homozygous for CaSR inactivating mutations have more severe hypercalcemia.^[19] Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia^[20] 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.^[21]

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.^[22] 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.^[23] 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.^{[24] [25]} 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,^{[26] [27] [28] [29]} 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.^[30]

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.

Interactions

Calcium-sensing receptor has been shown to interact with filamin.^{[31] [32]}

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.^[33] 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.^[34]

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.^[35]

Further reading

• Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE . Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia . Human Mutation . 16 . 4 . 281–296 . October 2000 . 11013439 . 10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A . 31157004 . free .
• Fukumoto S . [Calcium-sensing receptor in bone cells] . Nihon Rinsho. Japanese Journal of Clinical Medicine . 60 Suppl 3 . Suppl 3 . 57–63 . March 2002 . 11979955 .
• Tfelt-Hansen J, Schwarz P, Brown EM, Chattopadhyay N . The calcium-sensing receptor in human disease . Frontiers in Bioscience . 8 . 6 . s377–s390 . May 2003 . 12700051 . 10.2741/1068 . free .
• Hu J, Spiegel AM . Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function . Trends in Endocrinology and Metabolism . 14 . 6 . 282–288 . August 2003 . 12890593 . 10.1016/S1043-2760(03)00104-8 . 28822680 .
• Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T . 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 . September 1995 . 7673400 . 10.1210/jcem.80.9.7673400 .
• Aida K, Koishi S, Tawata M, Onaya T . Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney . Biochemical and Biophysical Research Communications . 214 . 2 . 524–529 . September 1995 . 7677761 . 10.1006/bbrc.1995.2318 .
• Chou YH, Pollak MR, Brandi ML, Toss G, Arnqvist H, Atkinson AB, Papapoulos SE, Marx S, Brown EM, Seidman JG . Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia . American Journal of Human Genetics . 56 . 5 . 1075–1079 . May 1995 . 7726161 . 1801464 .
• Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F . Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs . The Journal of Biological Chemistry . 270 . 21 . 12919–12925 . May 1995 . 7759551 . 10.1074/jbc.270.21.12919 . free .
• Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG . Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation . Nature Genetics . 8 . 3 . 303–307 . November 1994 . 7874174 . 10.1038/ng1194-303 . 22941518 .
• Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG . Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism . Cell . 75 . 7 . 1297–1303 . December 1993 . 7916660 . 10.1016/0092-8674(93)90617-Y . 40886966 .
• Janicic N, Soliman E, Pausova Z, Seldin MF, Rivière M, Szpirer J, Szpirer C, Hendy GN . 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 . November 1995 . 8597637 . 10.1007/BF00539007 . 19835161 .
• Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S . Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor . The Journal of Clinical Investigation . 97 . 4 . 1085–1093 . February 1996 . 8613532 . 507156 . 10.1172/JCI118501 .
• Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP . Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism . The Journal of Clinical Investigation . 96 . 6 . 2683–2692 . December 1995 . 8675635 . 185975 . 10.1172/JCI118335 .
• Bai M, Quinn S, Trivedi S, Kifor O, Pearce SH, Pollak MR, Krapcho K, Hebert SC, Brown EM . Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor . The Journal of Biological Chemistry . 271 . 32 . 19537–19545 . August 1996 . 8702647 . 10.1074/jbc.271.32.19537 . free .
• Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmerman D, Cutler GB . Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism . Human Molecular Genetics . 5 . 5 . 601–606 . May 1996 . 8733126 . 10.1093/hmg/5.5.601 .
• Freichel M, Zink-Lorenz A, Holloschi A, Hafner M, Flockerzi V, Raue F . 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 . September 1996 . 8756555 . 10.1210/endo.137.9.8756555 . free .
• Chattopadhyay N, Ye C, Singh DP, Kifor O, Vassilev PM, Shinohara T, Chylack LT, Brown EM . Expression of extracellular calcium-sensing receptor by human lens epithelial cells . Biochemical and Biophysical Research Communications . 233 . 3 . 801–805 . April 1997 . 9168937 . 10.1006/bbrc.1997.6553 .
• Cole DE, Janicic N, Salisbury SR, Hendy GN . 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 . August 1997 . 9217223 . 10.1002/(SICI)1096-8628(19970808)71:2<202::AID-AJMG16>3.0.CO;2-I .
• Ward BK, Stuckey BG, Gutteridge DH, Laing NG, Pullan PT, Ratajczak T . A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with familial hypocalciuric hypercalcemia . Human Mutation . 10 . 3 . 233–235 . 1997 . 9298824 . 10.1002/(SICI)1098-1004(1997)10:3<233::AID-HUMU9>3.0.CO;2-J . 34382961 . free .
• Quinn SJ, Kifor O, Trivedi S, Diaz R, Vassilev P, Brown E . Sodium and ionic strength sensing by the calcium receptor . The Journal of Biological Chemistry . 273 . 31 . 19579–19586 . July 1998 . 9677383 . 10.1074/jbc.273.31.19579 . free .
• Magno AL, Ward BK, Ratajczak T . The calcium-sensing receptor: a molecular perspective . Endocrine Reviews . 32 . 1 . 3–30 . February 2011 . 20729338 . 10.1210/er.2009-0043 . free .

External links

• Web site: Calcium-Sensing Receptors . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-10-25 . 2016-03-03 . https://web.archive.org/web/20160303203259/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1322 . dead .
• CASRdb - Calcium Sensing Receptor Database, McGill University

Notes and References

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6. 1994. Cloning and characterization of an extracellular Ca²⁺ -sensing receptor from parathyroid and kidney: new insights into the physiology and pathophysiology of calcium metabolism. Nephrology Dialysis Transplantation. 10.1093/ndt/9.12.1703. 1460-2385. free.
7. Aida K, Koishi S, Tawata M, Onaya T . Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney . Biochemical and Biophysical Research Communications . 214 . 2 . 524–529 . September 1995 . 7677761 . 10.1006/bbrc.1995.2318 .
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