Protein

Extracellular calcium-sensing receptor

Gene

CASR

Organism

Homo sapiens (Human)

Status

Reviewed-Annotation score: -Experimental evidence at protein levelⁱ

Functionⁱ

G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (PubMed:7759551, PubMed:8702647, PubMed:8636323, PubMed:8878438, PubMed:17555508, PubMed:19789209, PubMed:21566075, PubMed:22114145, PubMed:23966241, PubMed:25292184, PubMed:25104082, PubMed:26386835, PubMed:25766501, PubMed:22789683). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system (PubMed:7759551). The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (PubMed:27434672, PubMed:27386547).By similarity16 Publications

Enzyme regulationⁱ

In resting state, adopts an open conformation, anion-binding promoting the inactive configuration (PubMed:27434672). Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits (PubMed:27434672, PubMed:27386547). Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor (PubMed:27434672, PubMed:27386547). Activated by AMG 416, a D-amino acid-containing peptide agonist that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis (PubMed:26290606). AMG 416 agonist acts by forming a disulfide bond with Cys-482 (PubMed:26290606).3 Publications

Sites

Feature key	Position(s)	DescriptionActions	Length
Metal bindingⁱ	81	Calcium; via carbonyl oxygenCombined sources1 Publication1 Publication	1
Metal bindingⁱ	84	CalciumCombined sources1 Publication1 Publication	1
Metal bindingⁱ	87	Calcium; via carbonyl oxygenCombined sources1 Publication1 Publication	1
Metal bindingⁱ	88	Calcium; via carbonyl oxygenCombined sources1 Publication1 Publication	1
Metal bindingⁱ	100	CalciumCombined sources1 Publication	1
Metal bindingⁱ	145	CalciumCombined sources1 Publication	1
Binding siteⁱ	147	Aromatic amino acidCombined sources2 Publications	1
Binding siteⁱ	168	Aromatic amino acid; via carbonyl oxygenCombined sources2 Publications	1
Binding siteⁱ	170	Aromatic amino acidCombined sources2 Publications	1
Metal bindingⁱ	231	CalciumCombined sources1 Publication	1
Metal bindingⁱ	234	CalciumCombined sources1 Publication	1
Binding siteⁱ	297	Aromatic amino acidCombined sources2 Publications	1
Siteⁱ	482	Important for ability of agonist AMG 416 to activate G-protein-coupled receptor activity1 Publication	1
Metal bindingⁱ	557	Calcium; via carbonyl oxygenCombined sources1 Publication	1

GO - Molecular functionⁱ

amino acid binding
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
calcium ion binding
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
drug binding Source: Ensembl
G-protein coupled receptor activity
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
integrin binding Source: Ensembl
ion channel binding Source: Ensembl
magnesium ion binding Source: Ensembl
phosphatidylinositol phospholipase C activity
Source: ProtInc
Traceable author statementⁱ
- 7874174
polyamine binding Source: Ensembl
protein homodimerization activity
Source: UniProtKB
Inferred from direct assayⁱ
- 16740594
- 27434672
protein kinase binding Source: Ensembl

View the complete GO annotation on QuickGO ...

GO - Biological processⁱ

adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway Source: Ensembl
anatomical structure morphogenesis
Source: ProtInc
Traceable author statementⁱ
- 7916660
apoptotic process Source: Ensembl
branching morphogenesis of an epithelial tube Source: Ensembl
calcium ion import
Source: UniProtKB
Inferred from direct assayⁱ
- 20846291
cellular calcium ion homeostasis
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
cellular response to glucose stimulus Source: Ensembl
cellular response to hepatocyte growth factor stimulus Source: Ensembl
cellular response to hypoxia Source: Ensembl
cellular response to low-density lipoprotein particle stimulus Source: Ensembl
cellular response to peptide Source: Ensembl
cellular response to vitamin D Source: Ensembl
chemosensory behavior
Source: ProtInc
Traceable author statementⁱ
- 7759551
detection of calcium ion
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
fat pad development Source: Ensembl
G-protein coupled receptor signaling pathway
Source: UniProtKB
Inferred from direct assayⁱ
- 27434672
JNK cascade Source: Ensembl
ossification
Source: ProtInc
Traceable author statementⁱ
- 7874174
phospholipase C-activating G-protein coupled receptor signaling pathway Source: Ensembl
positive regulation of ATPase activity Source: Ensembl
positive regulation of calcium ion import Source: Ensembl
positive regulation of cell proliferation Source: Ensembl
positive regulation of gene expression Source: Ensembl
positive regulation of insulin secretion Source: Ensembl
positive regulation of positive chemotaxis Source: Ensembl
positive regulation of vasoconstriction Source: Ensembl
response to fibroblast growth factor Source: Ensembl
response to ischemia Source: Ensembl
vasodilation Source: Ensembl

View the complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	G-protein coupled receptor, Receptor, Transducer
Ligand	Calcium, Metal-binding

Enzyme and pathway databases

Reactomeⁱ	R-HSA-416476 G alpha (q) signalling events R-HSA-418594 G alpha (i) signalling events R-HSA-420499 Class C/3 (Metabotropic glutamate/pheromone receptors)
SIGNORⁱ	P41180

Protein family/group databases

TCDBⁱ	9.A.14.7.2 the g-protein-coupled receptor (gpcr) family

TCDBⁱ

9.A.14.7.2 the g-protein-coupled receptor (gpcr) family

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: Extracellular calcium-sensing receptorCurated Short name: CaR2 Publications Short name: CaSR Short name: hCasR1 Publication Alternative name(s): Parathyroid cell calcium-sensing receptor 11 Publication Short name: PCaR11 Publication
Gene namesⁱ	Name:CASRImported Synonyms:GPRC2A, PCAR11 Publication
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 3

Organism-specific databases

EuPathDBⁱ	HostDB:ENSG00000036828.13
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:1514 CASR
MIMⁱ	601199 gene+phenotype
neXtProtⁱ	NX_P41180

Topology

Feature key	Position(s)	DescriptionActions	Length
Topological domainⁱ	20 – 612	ExtracellularSequence analysisAdd BLAST	593
Transmembraneⁱ	613 – 635	Helical; Name=1Sequence analysisAdd BLAST	23
Topological domainⁱ	636 – 649	CytoplasmicSequence analysisAdd BLAST	14
Transmembraneⁱ	650 – 670	Helical; Name=2Sequence analysisAdd BLAST	21
Topological domainⁱ	671 – 681	ExtracellularSequence analysisAdd BLAST	11
Transmembraneⁱ	682 – 700	Helical; Name=3Sequence analysisAdd BLAST	19
Topological domainⁱ	701 – 724	CytoplasmicSequence analysisAdd BLAST	24
Transmembraneⁱ	725 – 745	Helical; Name=4Sequence analysisAdd BLAST	21
Topological domainⁱ	746 – 769	ExtracellularSequence analysisAdd BLAST	24
Transmembraneⁱ	770 – 792	Helical; Name=5Sequence analysisAdd BLAST	23
Topological domainⁱ	793 – 805	CytoplasmicSequence analysisAdd BLAST	13
Transmembraneⁱ	806 – 828	Helical; Name=6Sequence analysisAdd BLAST	23
Topological domainⁱ	829 – 836	ExtracellularSequence analysis	8
Transmembraneⁱ	837 – 862	Helical; Name=7Sequence analysisAdd BLAST	26
Topological domainⁱ	863 – 1078	CytoplasmicSequence analysisAdd BLAST	216

Keywords - Cellular componentⁱ

Cell membrane, Membrane

Pathology & Biotechⁱ

Involvement in diseaseⁱ

Hypocalciuric hypercalcemia, familial 1 (HHC1)26 Publications

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults.

See also OMIM:145980

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_058046	11	L → S in HHC1; demonstrates reduced intracellular and plasma membrane expression and signaling to the MAPK pathway in response to extracellular calcium relative to wild-type; fails to be inserted in the microsomes and does not undergo proper glycosylation. 1 PublicationCorresponds to variant dbSNP:rs200673016Ensembl.	1
Natural variantⁱVAR_058047	13	L → P in HHC1; has a dose-response curve shifted to the right relative to that of wild-type; demonstrates reduced intracellular and plasma membrane expression and signaling to the MAPK pathway in response to extracellular calcium relative to wild-type; fails to be inserted in the microsomes and does not undergo proper glycosylation. 2 PublicationsCorresponds to variant dbSNP:rs104893717EnsemblClinVar.	1
Natural variantⁱVAR_058049	21	G → R in HHC1. 1 Publication	1
Natural variantⁱVAR_003585	39	P → A in HHC1. 1 PublicationCorresponds to variant dbSNP:rs121909262EnsemblClinVar.	1
Natural variantⁱVAR_078139	42	F → S in HHC1. 1 Publication	1
Natural variantⁱVAR_078140	53	S → P in HHC1; decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_078141	55	P → L in HHC1; decreased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs886041154EnsemblClinVar.	1
Natural variantⁱVAR_003586	62	R → M in HHC1; mild; decreased G-protein coupled receptor signaling pathway. 2 PublicationsCorresponds to variant dbSNP:rs121909265EnsemblClinVar.	1
Natural variantⁱVAR_003587	66	R → C in HHC1; does not affect homodimerization; impaired N-glycosylation; impaired cell membrane localization; decreased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs121909266EnsemblClinVar.	1
Natural variantⁱVAR_078142	66	R → H in HHC1; does not affect homodimerization; impaired N-glycosylation; impaired cell membrane localization; decreased G-protein coupled receptor signaling pathway. 3 Publications	1
Natural variantⁱVAR_078143	81	I → M in HHC1; decreased G-protein coupled receptor signaling pathway. 2 Publications	1
Natural variantⁱVAR_078144	110	A → T in HHC1; decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_003590	138	T → M in HHC1; decreased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs121909263EnsemblClinVar.	1
Natural variantⁱVAR_003591	143	G → E in HHC1; decreased G-protein coupled receptor signaling pathway. 2 PublicationsCorresponds to variant dbSNP:rs121909264EnsemblClinVar.	1
Natural variantⁱVAR_078149	143	G → R in HHC1. 1 PublicationCorresponds to variant dbSNP:rs769256610EnsemblClinVar.	1
Natural variantⁱVAR_078150	158	G → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078151	159	L → P in HHC1; decreased G-protein coupled receptor signaling pathway. 2 Publications	1
Natural variantⁱVAR_078152	166	S → G in HHC1. 1 PublicationCorresponds to variant dbSNP:rs193922441EnsemblClinVar.	1
Natural variantⁱVAR_058056	171	S → N in HHC1. 1 Publication	1
Natural variantⁱVAR_078153	172	R → G in HHC1; decreased G-protein coupled receptor signaling pathway. 2 Publications	1
Natural variantⁱVAR_003592	174	L → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078154	178	N → D in HHC1; decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_058057	180	F → C in HHC1; although the mutant receptor is expressed normally at the cell surface it is unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. 1 PublicationCorresponds to variant dbSNP:rs121909268EnsemblClinVar.	1
Natural variantⁱVAR_003593	185	R → Q in HHC1; decreased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs104893689EnsemblClinVar.	1
Natural variantⁱVAR_078155	215	D → G in HHC1; decreased G-protein coupled receptor signaling pathway. 2 Publications	1
Natural variantⁱVAR_078156	220	R → W in HHC1. 1 Publication	1
Natural variantⁱVAR_058059	221	P → Q in HHC1. 1 PublicationCorresponds to variant dbSNP:rs397514728EnsemblClinVar.	1
Natural variantⁱVAR_078158	221	P → S in HHC1; decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_058060	225	K → T in HHC1. 1 Publication	1
Natural variantⁱVAR_003595	227	R → Q in HHC1; G-protein coupled receptor signaling pathway; less markedly impaired relative to wild-type than L-227; does not affect cell membrane localization. 2 PublicationsCorresponds to variant dbSNP:rs28936684EnsemblClinVar.	1
Natural variantⁱVAR_058062	271	S → F in HHC1. 1 Publication	1
Natural variantⁱVAR_003596	297	E → K in HHC1; decreased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs121909259EnsemblClinVar.	1
Natural variantⁱVAR_058063	397	G → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078160	459	Q → R in HHC1; decreased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 1 Publication	1
Natural variantⁱVAR_058064	465	R → Q in HHC1; loss-of-function mutation; the quantity of the mutant receptor is higher than that of the wild-type receptor; dose-response curves show that the mutation significantly reduces the sensitivity of the receptor to extracellular calcium concentrations. 1 PublicationCorresponds to variant dbSNP:rs104893716EnsemblClinVar.	1
Natural variantⁱVAR_058065	509	G → R in HHC1. 1 PublicationCorresponds to variant dbSNP:rs193922423EnsemblClinVar.	1
Natural variantⁱVAR_078161	549	G → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078162	550	T → I in HHC1; decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_058066	553	G → R in HHC1. 1 PublicationCorresponds to variant dbSNP:rs104893719EnsemblClinVar.	1
Natural variantⁱVAR_058067	555	I → V in HHC1. 1 PublicationCorresponds to variant dbSNP:rs777646067Ensembl.	1
Natural variantⁱVAR_012649	557	G → E in HHC1; Abolished G-protein coupled receptor activity. 2 Publications	1
Natural variantⁱVAR_058068	562	C → Y in HHC1. 2 Publications	1
Natural variantⁱVAR_078164	565	C → G in HHC1. 1 Publication	1
Natural variantⁱVAR_078166	571	G → W in HHC1; decreased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 1 Publication	1
Natural variantⁱVAR_058069	582	C → F in HHC1. 1 PublicationCorresponds to variant dbSNP:rs104893690EnsemblClinVar.	1
Natural variantⁱVAR_078167	583 – 1078	Missing in HHC1; impaired homodimerization; impaired cell membrane localization. 2 PublicationsAdd BLAST	496
Natural variantⁱVAR_058072	623	G → D in HHC1. 1 Publication	1
Natural variantⁱVAR_078168	657	S → Y in HHC1. 1 Publication	1
Natural variantⁱVAR_078169	661	C → Y in HHC1. 1 Publication	1
Natural variantⁱVAR_058074	670	G → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078170	680	R → H in HHC1. 1 PublicationCorresponds to variant dbSNP:rs773146939EnsemblClinVar.	1
Natural variantⁱVAR_065494	697	V → M in HHC1. 1 Publication	1
Natural variantⁱVAR_078172	707	E → V in HHC1; decreased protein level. 1 Publication	1
Natural variantⁱVAR_058076	728	V → F in HHC1. 1 Publication	1
Natural variantⁱVAR_058077	742	W → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078173	748	P → R in HHC1. 1 Publication	1
Natural variantⁱVAR_078174	761	Missing in HHC1. 1 Publication	1
Natural variantⁱVAR_078175	774	G → S in HHC1; decreased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 1 Publication	1
Natural variantⁱVAR_003599	795	R → W in HHC1; decreased G-protein coupled receptor signaling pathway. 4 PublicationsCorresponds to variant dbSNP:rs121909258EnsemblClinVar.	1
Natural variantⁱVAR_078177	802	N → S in HHC1; decreased G-protein coupled receptor signaling pathway. 1 PublicationCorresponds to variant dbSNP:rs140022350EnsemblClinVar.	1
Natural variantⁱVAR_078178	817	V → I in HHC1; decreased G-protein coupled receptor signaling pathway. 1 PublicationCorresponds to variant dbSNP:rs1057518933Ensembl.	1
Natural variantⁱVAR_058084	886	R → W in HHC1. 1 Publication	1
Natural variantⁱVAR_078183	972	T → M in HHC1; decreased G-protein coupled receptor signaling pathway. 1 PublicationCorresponds to variant dbSNP:rs200620134EnsemblClinVar.	1

Hyperparathyroidism, neonatal severe (NSHPT)7 Publications

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy.

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_065199	100	T → I in NSHPT; Abolished G-protein coupled receptor activity. 2 Publications	1
Natural variantⁱVAR_003594	227	R → L in NSHPT; decreased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 4 PublicationsCorresponds to variant dbSNP:rs28936684EnsemblClinVar.	1
Natural variantⁱVAR_065200	336	Missing in NSHPT. 1 Publication	1
Natural variantⁱVAR_078163	551	R → K in NSHPT; decreased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 2 Publications	1
Natural variantⁱVAR_065202	650	L → P in NSHPT. 1 Publication	1
Natural variantⁱVAR_058073	670	G → E in NSHPT. 1 PublicationCorresponds to variant dbSNP:rs104893700EnsemblClinVar.	1
Natural variantⁱVAR_065203	689	V → M in NSHPT. 1 Publication	1

Hypocalcemia, autosomal dominant 1 (HYPOC1)21 Publications

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia.

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_058050	47	K → N in HYPOC1; the EC(50) of the mutant is significantly lower than that of wild-type. 1 PublicationCorresponds to variant dbSNP:rs104893702EnsemblClinVar.	1
Natural variantⁱVAR_003588	116	A → T in HYPOC1. 1 PublicationCorresponds to variant dbSNP:rs104893691EnsemblClinVar.	1
Natural variantⁱVAR_058051	118	N → K in HYPOC1; the mutation shifts the concentration-response curve to the left and increases maximal activity. 3 PublicationsCorresponds to variant dbSNP:rs104893695EnsemblClinVar.	1
Natural variantⁱVAR_078145	122	S → C in HYPOC1; increased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_078146	125	L → F in HYPOC1. 1 Publication	1
Natural variantⁱVAR_058052	125	L → P in HYPOC1; shifts the concentration-response curve of calcium ions to the left. 1 PublicationCorresponds to variant dbSNP:rs104893708EnsemblClinVar.	1
Natural variantⁱVAR_003589	127	E → A in HYPOC1; increased G-protein coupled receptor signaling pathway. 2 PublicationsCorresponds to variant dbSNP:rs121909260EnsemblClinVar.	1
Natural variantⁱVAR_058053	128	F → L in HYPOC1; increased G-protein coupled receptor signaling pathway. 2 PublicationsCorresponds to variant dbSNP:rs104893696EnsemblClinVar.	1
Natural variantⁱVAR_078147	129	C → R in HYPOC1. 1 Publication	1
Natural variantⁱVAR_058054	131	C → W in HYPOC1; associated with clinical features of Bartter syndrome. 1 PublicationCorresponds to variant dbSNP:rs121909267EnsemblClinVar.	1
Natural variantⁱVAR_078148	136	P → L in HYPOC1; increased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 1 Publication	1
Natural variantⁱVAR_058055	151	T → M in HYPOC1; increased G-protein coupled receptor signaling pathway. 3 PublicationsCorresponds to variant dbSNP:rs104893694EnsemblClinVar.	1
Natural variantⁱVAR_058058	191	E → K in HYPOC1; increased G-protein coupled receptor signaling pathway. 2 PublicationsCorresponds to variant dbSNP:rs104893697EnsemblClinVar.	1
Natural variantⁱVAR_078157	221	P → L in HYPOC1. 1 PublicationCorresponds to variant dbSNP:rs397514728EnsemblClinVar.	1
Natural variantⁱVAR_078159	228	E → K in HYPOC1. 1 Publication	1
Natural variantⁱVAR_078165	569	P → H in HYPOC1; increased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_058070	604	E → K in HYPOC1; there is a significant leftward shift in the concentration response curves for the effects of extracellular calcium on both intracellular calcium mobilization and MAPK activity. 2 PublicationsCorresponds to variant dbSNP:rs104893712EnsemblClinVar.	1
Natural variantⁱVAR_058071	612	F → S in HYPOC1. 1 PublicationCorresponds to variant dbSNP:rs104893698EnsemblClinVar.	1
Natural variantⁱVAR_015414	616	L → V in HYPOC1; does not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected cells. 1 PublicationCorresponds to variant dbSNP:rs104893703EnsemblClinVar.	1
Natural variantⁱVAR_003598	681	Q → H in HYPOC1. 1 PublicationCorresponds to variant dbSNP:rs121909261EnsemblClinVar.	1
Natural variantⁱVAR_078171	681	Q → R in HYPOC1; increased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 1 Publication	1
Natural variantⁱVAR_058075	727	L → Q in HYPOC1; increased G-protein coupled receptor signaling pathway; does not affect cell membrane localization. 2 PublicationsCorresponds to variant dbSNP:rs104893718EnsemblClinVar.	1
Natural variantⁱVAR_021019	767	E → K in HYPOC1. 1 Publication	1
Natural variantⁱVAR_058078	773	L → R in HYPOC1; the mutation shifts the concentration-response curve to the left and increases maximal activity. 1 PublicationCorresponds to variant dbSNP:rs104893699EnsemblClinVar.	1
Natural variantⁱVAR_058079	788	F → C in HYPOC1; leftward shift in the concentration-response curve for the mutant receptor; cells cotransfected with both the wild-type and the mutant receptor show an EC(50) similar to the mutant; a gain-of-function mutation rendering the receptor more sensitive than normal to activation. 1 PublicationCorresponds to variant dbSNP:rs104893701EnsemblClinVar.	1
Natural variantⁱVAR_058080	788	F → L in HYPOC1; induces a significant shift to the left relative to the wild-type protein in the MAPK response to increasing extracellular calcium concentrations. 1 PublicationCorresponds to variants dbSNP:rs886041537 and dbSNP:rs104893711EnsemblClinVarEnsembl.	1
Natural variantⁱVAR_078176	802	N → I in HYPOC1; increased G-protein coupled receptor signaling pathway. 2 Publications	1
Natural variantⁱVAR_003600	806	F → S in HYPOC1; does not produce a significant activating effect; decreased cell surface receptor expression. 2 PublicationsCorresponds to variant dbSNP:rs104893693EnsemblClinVar.	1
Natural variantⁱVAR_058081	820	S → F in HYPOC1; the concentration-response curve of the mutant receptor is left-shifted and its EC(50) is significantly lower than that of the wild-type. 1 PublicationCorresponds to variant dbSNP:rs104893710EnsemblClinVar.	1
Natural variantⁱVAR_078179	830	G → S in HYPOC1. 1 Publication	1
Natural variantⁱVAR_078180	832	F → L in HYPOC1. 1 Publication	1
Natural variantⁱVAR_078181	832	F → S in HYPOC1. 1 Publication	1
Natural variantⁱVAR_078182	839	I → T in HYPOC1; increased G-protein coupled receptor signaling pathway. 1 Publication	1
Natural variantⁱVAR_058082	843	A → E in HYPOC1; also in HYPOC1 associated with clinical features of Bartter syndrome; shifts the concentration-response curve of calcium ions to the left. 2 PublicationsCorresponds to variant dbSNP:rs104893706EnsemblClinVar.	1

Epilepsy, idiopathic generalized 8 (EIG8)1 Publication

Disease susceptibility is associated with variations affecting the gene represented in this entry.

Disease descriptionA disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures.

Feature key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_060206	354	E → A in EIG8; patients present juvenile myoclonus epilepsy. 1 Publication	1
Natural variantⁱVAR_060207	686	I → V in EIG8; patients present juvenile myoclonus epilepsy. 1 PublicationCorresponds to variant dbSNP:rs753013993EnsemblClinVar.	1
Natural variantⁱVAR_060208	898	R → Q in EIG8. 1 PublicationCorresponds to variant dbSNP:rs121909269EnsemblClinVar.	1
Natural variantⁱVAR_060209	988	A → G in EIG8; patients present juvenile myoclonus epilepsy. 1 Publication	1
Natural variantⁱVAR_060210	988	A → V in EIG8; patients present juvenile myoclonus epilepsy. 1 PublicationCorresponds to variant dbSNP:rs759027000Ensembl.	1

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	69	R → E: Abolishes G-protein coupled receptor signaling pathway. 1 Publication	1
Mutagenesisⁱ	102	N → I: Abolishes G-protein coupled receptor activity. 1 Publication	1
Mutagenesisⁱ	145	T → A: Abolishes G-protein coupled receptor activity. 1 Publication	1
Mutagenesisⁱ	147	S → A: Nearly abolished G-protein coupled receptor activity. 1 Publication	1
Mutagenesisⁱ	170	S → A: Abolishes G-protein coupled receptor activity. 1 Publication	1
Mutagenesisⁱ	218	Y → S: Abolishes G-protein coupled receptor activity. 1 Publication	1
Mutagenesisⁱ	297	E → I: Abolishes ability to sense calcium or magnesium levels. 1 Publication	1
Mutagenesisⁱ	417	S → L: Abolishes G-protein coupled receptor signaling pathway. 1 Publication	1
Mutagenesisⁱ	458	W → A: Decreased G-protein coupled receptor signaling pathway. 1 Publication	1
Mutagenesisⁱ	482	C → S or Y: Abolishes ability of agonist AMG 416 to activate G-protein-coupled receptor activity. 1 Publication	1

Keywords - Diseaseⁱ

Disease mutation, Epilepsy

Organism-specific databases

DisGeNET More...DisGeNETⁱ	846
MalaCards human disease database More...MalaCardsⁱ	CASR
MIMⁱ	145980 phenotype 239200 phenotype 601198 phenotype 601199 gene+phenotype 612899 phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000036828
Orphanetⁱ	428 Autosomal dominant hypocalcemia 263417 Bartter syndrome with hypocalcemia 93372 Familial hypocalciuric hypercalcemia type 1 189466 Familial isolated hypoparathyroidism due to impaired PTH secretion 417 Neonatal severe primary hyperparathyroidism
PharmGKBⁱ	PA26097

Chemistry databases

ChEMBLⁱ	CHEMBL1878
Drug and drug target database More...DrugBankⁱ	DB05255 751689 DB01012 Cinacalcet DB12865 Etelcalcetide
IUPHAR/BPS Guide to PHARMACOLOGY More...GuidetoPHARMACOLOGYⁱ	54

Polymorphism and mutation databases

BioMutaⁱ	CASR
DMDMⁱ	1168781

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Signal peptideⁱ	1 – 19	Sequence analysisAdd BLAST		19
ChainⁱPRO_0000012946	20 – 1078	Extracellular calcium-sensing receptorAdd BLAST		1059

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Disulfide bondⁱ	60 ↔ 101	Combined sources2 Publications
Glycosylationⁱ	90	N-linked (GlcNAc...) asparagineSequence analysis	1
Disulfide bondⁱ	129	Interchain1 Publication1 Publication
Glycosylationⁱ	130	N-linked (GlcNAc...) asparagineSequence analysis	1
Disulfide bondⁱ	131	Interchain1 Publication1 Publication
Disulfide bondⁱ	236 ↔ 561	1 Publication
Glycosylationⁱ	261	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Glycosylationⁱ	287	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Disulfide bondⁱ	358 ↔ 395	Combined sources2 Publications
Glycosylationⁱ	386	N-linked (GlcNAc...) asparagineSequence analysis	1
Glycosylationⁱ	400	N-linked (GlcNAc...) asparagineSequence analysis	1
Disulfide bondⁱ	437 ↔ 449	Combined sources2 Publications
Glycosylationⁱ	446	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Glycosylationⁱ	468	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Glycosylationⁱ	488	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Glycosylationⁱ	541	N-linked (GlcNAc...) asparagineSequence analysis1 Publication	1
Disulfide bondⁱ	542 ↔ 562	1 Publication
Disulfide bondⁱ	546 ↔ 565	1 Publication

UniProtKB - P41180 (CASR_HUMAN)

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Extracellular calcium-sensing receptor

CASR

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Functionⁱ

Enzyme regulationⁱ

Sites

GO - Molecular functionⁱ

GO - Biological processⁱ

Keywordsⁱ

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomyⁱ

Organism-specific databases

Subcellular locationⁱ

Plasma membrane

Nucleus

Plasma Membrane

Other locations

Topology

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

Involvement in diseaseⁱ

Hypocalciuric hypercalcemia, familial 1 (HHC1)26 Publications

Hyperparathyroidism, neonatal severe (NSHPT)7 Publications

Hypocalcemia, autosomal dominant 1 (HYPOC1)21 Publications

Epilepsy, idiopathic generalized 8 (EIG8)1 Publication

Mutagenesis

Keywords - Diseaseⁱ

Organism-specific databases

Chemistry databases

Polymorphism and mutation databases

PTM / Processingⁱ

Molecule processing

Amino acid modifications

UniProtKB

UniParc

Help

UniRef

Proteomes

Annotation systems

Supporting data

UniProtKB - P41180 (CASR_HUMAN)

Your basket is currently empty. i <p>When browsing through different UniProt proteins, you can use the ‘basket’ to save them, so that you can back to find or analyse them later.<p><a href='/help/basket' target='_top'>More...</a></p>

Extracellular calcium-sensing receptor

CASR

Select a section on the left to see content.

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

<p>This subsection of the ‘Function’ section describes an enzyme regulatory mechanism and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/enzyme_regulation' target='_top'>More...</a></p>Enzyme regulationi

Sites

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Biological processi

Enzyme and pathway databases

Protein family/group databases

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

Organism-specific databases

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Plasma membrane

Nucleus

Plasma Membrane

Other locations

Topology

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Organism-specific databases

Chemistry databases

Polymorphism and mutation databases

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Amino acid modifications

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Functionⁱ

Enzyme regulationⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Pathology & Biotechⁱ

PTM / Processingⁱ