The calcium-sensing receptor (CaSR) is a
Class C G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
which senses extracellular levels of
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
ions. It is primarily expressed in the
parathyroid gland
Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes pa ...
, the
renal tubules
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
of the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
and the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
. In the parathyroid gland, it controls calcium
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
by regulating the release of
parathyroid hormone
Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.
PTH influences bone re ...
(PTH).
In the kidney it has an inhibitory effect on the reabsorption of calcium,
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
,
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
, and water depending on which segment of the tubule is being activated.
Since the initial review of CaSR, 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. 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.
Signal transduction
The release of PTH is inhibited in response to elevations in plasma calcium concentrations and activation of the calcium receptor. Increased calcium binding on the extracellular side gives a conformational change in the receptor, which, on the intracellular side, initiates the
phospholipase C pathway,
presumably through a
Gqα type of G protein, which ultimately increases intracellular concentration of calcium, which inhibits
vesicle fusion Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles c ...
and exocytosis of parathyroid hormone. It also inhibits (not stimulates, as some
sources state) the
cAMP dependent pathway
In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.
Discovery
cAMP was discovered by Earl Sutherland ...
.
[
]
Pathology
Mutations that inactivate a CaSR gene cause familial hypocalciuric hypercalcemia
Familial hypocalciuric hypercalcemia (FHH) is an inherited condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL; although uncommon. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) whe ...
(FHH) (also known as familial benign hypercalcemia because it is generally asymptomatic and does not require treatment), when present in heterozygotes
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
. Patients who are homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for CaSR inactivating mutations have more severe hypercalcemia. Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia
Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol ...
or Type 5 Bartter syndrome
Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. Th ...
. An alternatively spliced
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
transcript variant encoding 1088 aa has been found for this gene, but its full-length nature has not been defined.
Therapeutic application
The drugs cinacalcet
Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat tertiary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism. Text was copied from this source which is © European Medicines Agenc ...
and etelcalcetide
Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelcal ...
are allosteric
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
modifiers of the calcium-sensing receptor. They are classified as a calcimimetic A calcimimetic is a pharmaceutical drug that mimics the action of calcium on tissues, by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. Calcimimetics are used to treat secondary hyperparathyro ...
s, binding to the calcium-sensing receptor and decreasing parathyroid hormone release.
Calcilytic Calcilytics are pharmaceutical drugs that act as antagonists at the calcium-sensing receptor (CaSR). This increases the secretion of parathyroid hormone (PTH), which has a temporary anabolic effect on bone tissue, producing an increase in both bone ...
drugs, which block CaSR, produce increased bone density in animal studies and have been researched for the treatment of osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
. Unfortunately clinical trial results in humans have proved disappointing, with sustained changes in bone density not observed despite the drug being well tolerated. More recent research has shown the CaSR receptor to be involved in numerous other conditions including Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
and some forms of cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, and calcilytic drugs are being researched as potential treatments for these. Recently it has been shown that biomimetic bone like apatite
Apatite is a group of phosphate minerals, usually hydroxyapatite, fluorapatite and chlorapatite, with high concentrations of OH−, F− and Cl− ions, respectively, in the crystal. The formula of the admixture of the three most common e ...
inhibits formation of bone through endochondral ossification
Endochondral ossification is one of the two essential processes during fetal development of the mammalian skeletal system by which bone tissue is produced. Unlike intramembranous ossification, the other process by which bone tissue is produced, c ...
pathway via hyperstimulation of extracellular calcium sensing receptor.
Interactions
Calcium-sensing receptor has been shown to interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with filamin Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids. ...
.
References
Further reading
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External links
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CASRdb - Calcium Sensing Receptor Database
McGill University
McGill University (french: link=no, Université McGill) is an English-language public research university located in Montreal, Quebec, Canada. Founded in 1821 by royal charter granted by King George IV,Frost, Stanley Brice. ''McGill Universit ...
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{{G protein-coupled receptors, g3
G protein-coupled receptors