id: PW:0001141 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001141 title: calcium signaling pathway via the calcium-sensing receptor description: 'Calcium (Ca2+) signaling via the calcium-sensing receptor (Casr) exerts important roles in calcium homeostasis; it inhibits the secretion of parathyroid hormone (PTH) in parathyroid glands and regulates calcium absorption and water balance in the kidney, the two tissues where the receptor is most abundantly expressed. The function of Casr is also important for the proper functioning of cells involved in bone remodeling and of many types of neural cells, among others. In addition to Ca2+, the receptor binds a number of agonists or ''calcimimetics'' of which those that activate the receptor independent of Ca2+ are referred to as type I or orthosteric agonists while those that require the metal ion acting as positive allosteric modulators (PAMs) are known as type II calcimimetics. At the other end of the spectrum are the ''calcilytics'' or the negative modulators (NAMs) of Casr. The receptor is a G-protein coupled receptor (GPCR) that belongs to the C group. Discovered in early 90s, it is believed to have evolved from a common ancestor that belonged to the bacterial nutrient periplasmic binding protein family. A feature of the large extracellular domain characteristic of group C proteins is the presence of the Venus flytrap (VFT) module with which the bacterial proteins share sequence similarity. The VFTM is a bi-lobed structure with a crevice in between involved in ligand recognition and undergoing conformational changes upon its binding. Residues critical for Ca2+ binding are within the crevice with two additional sites discovered, one in each lobe. Overall, the receptor binds cooperatively 3 to 5 metal ions. The extracellular domain is also the site of several cysteine residues, some of which have been shown to be important for the covalent disulfide bond of the obligate Casr dimer. Of note is that Casr can also heterodimerize with other C group GPCRs. Calcimimetics and calcilytics bind to/within the transmembrane domain to overlapping, but not identical sites. Casr exerts pleiotropic effects by engaging several alpha subunit types of heterotrimeric G proteins; its downstream signaling is complex and cell specific but many of its molecular underpinnings remain to be determined. CasR activates Galphai leading to inhibition of adenylyl cyclases and reduced production of cAMP. Activation of Galphaq type and subsequent activation of phospholipase C, leads to production of diacylglycerol (DAG) and activation of PKC signaling and to production of inositol 1,4,5-triphosphate (IP3) and subsequent release of Ca2+ from intracellular stores. PKC is believed to provide a negative regulatory loop as Casr activated PKC may in turn phosphorylate and inhibit the receptor which contains several putative PKC binding sites. Casr may also activate the Galpha12/13 pathway. Note that Casr switches from Galphai coupling in normal mammary epithelial cells to Galphas in breast cancer cell lines. Downstream MAPK pathways are triggered in response to Casr activation, particularly the one mediated by Erk1/2; results support the view that both Galphaq and Galphai pathways are involved. The monomeric G protein Rho/Rac/Cdc42 pathway is also activated downstream of either Galphaq or Galpha12/13, depending on the system. Filamin A (Flna) binds to the intracellular tail of Casr and is believed to act as a scaffold coupling Galpha subunits and RhoA (a complex of Casr, RhoA, flna and Lbc (a guanyl-nucleotide exchange factor (GEF) for Rho) can be immunoprecipitated). Several other interacting partners have been identified but their functional relevance remains to be established (selected partners are listed in the accompanying link, but they are not annotated to the term). The G-protein coupled kinases (GRKs) and beta-arrestins partners are known components of GPCRs mediated pathways: GRKs phosphorylate the activated receptor which is then recognized by beta-arrestins whose binding precludes the association of the receptor with G proteins (receptor desensitization). Beta-arrestins have been shown to promote activation of Erk1/2 pathway downstream of Casr . The regulators of G protein signaling (RGS) proteins act as GTP activating proteins (GAP) that accelerate GTP hydrolysis resulting in inactivation of the Galpha subunit and termination of signaling: several inhibit Casr mediated signaling. Loss-of-function or inactivating as well as activating, gain-of function mutations have been identified; many but not all are located in the extracellular domain of the receptor. Additional information can be found at the CaSR database .' diagram_image: https://rgd.mcw.edu/pathway/PW0001141/calcium%20signaling%20pathway%20via%20the%20calcium-sensing%20receptor/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001141/calcium%20signaling%20pathway%20via%20the%20calcium-sensing%20receptor/calcium%20signaling%20pathway%20via%20the%20calcium-sensing%20receptor.gpp diagram_pathway_links: - id: PW:0000102 label: the extracellular signal-regulated Raf/Mek/Erk signaling pathway - id: PW:0000105 label: Rho/Rac/Cdc42 mediated signaling pathway - id: PW:0000228 label: G protein mediated signaling pathway via Galphai family - id: PW:0000229 label: G protein mediated signaling pathway via Galphaq family - id: PW:0000230 label: G protein mediated signaling pathway via Galpha12/Galpha13 family - id: PW:0000840 label: protein kinase C (PKC) signaling pathway - id: PW:0001135 label: parathyroid hormone signaling pathway diagram_gene_links: - id: RGD:2156 label: Arrb1 - id: RGD:2157 label: Arrb2 - id: RGD:2277 label: Casr - id: RGD:1560614 label: Flna - id: RGD:619921 label: Rhoa diagram_chemicals: - id: CHEBI:29108 label: Ca2+ - id: PUBCHEM.COMPOUND:6026790 label: DAG - id: CHEBI:16595 label: IP3 diagram_edges: - source: Arrb1 relation: associated_with target: Casr - source: Arrb2 relation: associated_with target: Casr - source: Ca2+ relation: associated_with target: Casr - source: Casr relation: associated_with target: Casr binding partners - source: Casr relation: associated_with target: Flna - source: Casr relation: negatively_affects target: PTH secretion - source: Casr relation: negatively_affects target: parathyroid hormone signaling pathway - source: Casr relation: positively_affects target: Ca absoprtion, water balance - source: G protein mediated signaling pathway via Galphai family relation: positively_affects target: inhibition of adenylyl cyclases/decreased cAMP - source: G protein mediated signaling pathway via Galphaq family relation: positively_affects target: increased DAG/IP3 via PLC activation - source: GRKs relation: negatively_affects target: Casr - source: RGS proteins relation: negatively_affects target: G protein mediated signaling pathway via Galpha12/Galpha13 family - source: RGS proteins relation: negatively_affects target: G protein mediated signaling pathway via Galphai family - source: RGS proteins relation: negatively_affects target: G protein mediated signaling pathway via Galphaq family - source: calcilytics relation: associated_with target: Casr - source: calcilytics relation: negatively_affects target: Casr - source: calcimimetics relation: associated_with target: Casr diagram_labels: - Arrb1 --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - Arrb2 --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - Ca absoprtion, water balance - calcimimetics --+> Casr - Casr --+> G protein mediated signaling pathway via Galpha12/Galpha13 family - Casr --+> G protein mediated signaling pathway via Galphai family - Casr --+> G protein mediated signaling pathway via Galphaq family - G protein mediated signaling pathway via Galpha12/Galpha13 family --+> Rho/Rac/Cdc42 mediated signaling pathway - G protein mediated signaling pathway via Galphai family --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - G protein mediated signaling pathway via Galphaq family --+> Rho/Rac/Cdc42 mediated signaling pathway - G protein mediated signaling pathway via Galphaq family --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway - increased DAG/IP3 via PLC activation - increased DAG/IP3 via PLC activation --+> protein kinase C (PKC) signaling pathway - inhibition of adenylyl cyclases/decreased cAMP - PTH secretion - receptor desensitization diagram_other_links: - href: /wg/home/pathway2/casr-binding-partners label: Casr binding partners - href: /wg/home/pathway2/molecular-pathways2/calcilytics label: calcilytics - href: /wg/home/pathway2/molecular-pathways2/calcimimetics label: calcimimetics - href: /wg/home/pathway2/molecular-pathways2/grks label: GRKs - href: /wg/home/pathway2/molecular-pathways2/rgs-proteins label: RGS proteins references: - id: RGD:7207059 citation: 'Thomsen AR, etal., Cell Calcium. 2012 Feb;51(2):107-16. doi: 10.1016/j.ceca.2011.11.009. 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