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Calcium-sensing receptor

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CASR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCASR, CAR, EIG8, FHH, FIH, GPRC2A, HHC, HHC1, HYPOC1, NSHPT, PCAR1, calcium sensing receptor, hCasR, Calcium-sensing receptor+CaSR
External IDsOMIM: 601199; MGI: 1351351; HomoloGene: 332; GeneCards: CASR; OMA:CASR - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 16: 36.31 – 36.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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

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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

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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

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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

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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

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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 Gqα 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

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Agonists

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Positive allosteric modulators

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Antagonists

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  • Calcilytics
  • Phosphate[20]

Negative allosteric modulators

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  • 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

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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

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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

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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

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

Role in sensory evaluation of food

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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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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000036828 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051980 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Yano S, Brown EM, Chattopadhyay N (March 2004). "Calcium-sensing receptor in the brain". Cell Calcium. 35 (3): 257–264. doi:10.1016/j.ceca.2003.10.008. PMID 15200149.
  6. ^ Giudice ML, Mihalik B, Dinnyés A, Kobolák J (July 2019). "The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease". Molecules. 24 (14): 2546. doi:10.3390/molecules24142546. PMC 6680999. PMID 31336912.
  7. ^ D'Souza-Li L (August 2006). "The calcium-sensing receptor and related diseases". Arquivos Brasileiros de Endocrinologia e Metabologia. 50 (4): 628–639. doi:10.1590/S0004-27302006000400008. PMID 17117288.
  8. ^ Vezzoli G, Soldati L, Gambaro G (April 2009). "Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport". Current Pharmaceutical Biotechnology. 10 (3): 302–310. doi:10.2174/138920109787847475. PMID 19355940.
  9. ^ Brown EM, Pollak M, Riccardi D, Hebert SC (1994). "Cloning and characterization of an extracellular Ca(2+)-sensing receptor from parathyroid and kidney: new insights into the physiology and pathophysiology of calcium metabolism". Nephrology, Dialysis, Transplantation. 9 (12): 1703–1706. PMID 7708247.
  10. ^ "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. 1994. doi:10.1093/ndt/9.12.1703. ISSN 1460-2385.
  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. ^ a b c 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.
  14. ^ Koehl A, Hu H, Feng D, Sun B, Zhang Y, Robertson MJ, et al. (February 2019). "Structural insights into the activation of metabotropic glutamate receptors". Nature. 566 (7742): 79–84. Bibcode:2019Natur.566...79K. doi:10.1038/s41586-019-0881-4. PMC 6709600. PMID 30675062.
  15. ^ InterPro: IPR000068 GPCR, family 3, extracellular calcium-sensing receptor-related Retrieved on June 2, 2009
  16. ^ a b Coburn JW, Elangovan L, Goodman WG, Frazaõ JM (December 1999). "Calcium-sensing receptor and calcimimetic agents". Kidney International. Supplement. 73: S52–S58. doi:10.1046/j.1523-1755.1999.07303.x. PMID 10633465.
  17. ^ Costanzo LS (2007). BRS Physiology (Board Review Series). Lippincott Williams & Wilkins. pp. 260. ISBN 978-0-7817-7311-9.
  18. ^ a b 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. ^ a b 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. ^ a b 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

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