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Calcium-sensing receptor
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Calcium-sensing receptor
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, pancreatic islets and the brain. In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). In the kidney, it has an inhibitory effect on the re-absorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated. CaSR has regulatory role in insulin secretion, adhesion and beta-cell proliferation in pancreatic islets.
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.
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.
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
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.
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Calcium-sensing receptor
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, pancreatic islets and the brain. In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). In the kidney, it has an inhibitory effect on the re-absorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated. CaSR has regulatory role in insulin secretion, adhesion and beta-cell proliferation in pancreatic islets.
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.
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.
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
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.
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