CASR_HUMAN
ID CASR_HUMAN Reviewed; 1078 AA.
AC P41180; Q13912; Q16108; Q16109; Q16110; Q16379; Q2M1T0; Q4PJ19;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2017, sequence version 3.
DT 03-AUG-2022, entry version 219.
DE RecName: Full=Extracellular calcium-sensing receptor {ECO:0000305};
DE Short=CaR {ECO:0000303|PubMed:7759551, ECO:0000303|PubMed:8813042};
DE Short=CaSR;
DE Short=hCasR {ECO:0000303|PubMed:27386547};
DE AltName: Full=Parathyroid cell calcium-sensing receptor 1 {ECO:0000303|PubMed:8698326};
DE Short=PCaR1 {ECO:0000303|PubMed:8698326};
DE Flags: Precursor;
GN Name=CASR {ECO:0000312|HGNC:HGNC:1514};
GN Synonyms=GPRC2A, PCAR1 {ECO:0000303|PubMed:8698326};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HYPOC1 LYS-118; LEU-128;
RP MET-151; LYS-191 AND SER-612, AND CHARACTERIZATION OF VARIANTS HYPOC1
RP LEU-128; MET-151 AND LYS-191.
RX PubMed=8813042; DOI=10.1056/nejm199610103351505;
RA Pearce S.H.S., Williamson C., Kifor O., Bai M., Coulthard M.G., Davies M.,
RA Lewis-Barned N., McCredie D., Powell H., Kendall-Taylor P., Brown E.M.,
RA Thakker R.V.;
RT "A familial syndrome of hypocalcemia with hypercalciuria due to mutations
RT in the calcium-sensing receptor.";
RL N. Engl. J. Med. 335:1115-1122(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, AND VARIANT
RP GLY-990.
RC TISSUE=Parathyroid;
RX PubMed=7759551; DOI=10.1074/jbc.270.21.12919;
RA Garrett J.E., Capuano I.V., Hammerland L.G., Hung B.C., Brown E.M.,
RA Hebert S.C., Nemeth E.F., Fuller F.;
RT "Molecular cloning and functional expression of human parathyroid calcium
RT receptor cDNAs.";
RL J. Biol. Chem. 270:12919-12925(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RX PubMed=7677761; DOI=10.1006/bbrc.1995.2318;
RA Aida K., Koishi S., Tawata M., Onaya T.;
RT "Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human
RT kidney.";
RL Biochem. Biophys. Res. Commun. 214:524-529(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8756555; DOI=10.1210/endo.137.9.8756555;
RA Freichel M., Zink-Lorenz A., Holloschi A., Hafner M., Flockerzi V.,
RA Raue F.;
RT "Expression of a calcium-sensing receptor in a human medullary thyroid
RT carcinoma cell line and its contribution to calcitonin secretion.";
RL Endocrinology 137:3842-3848(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-986; GLY-990 AND
RP GLN-1011.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-61, AND VARIANT HHC1 ALA-39.
RX PubMed=7673400; DOI=10.1210/jcem.80.9.7673400;
RA Aida K., Koishi S., Inoue M., Nakazato M., Tawata M., Onaya T.;
RT "Familial hypocalciuric hypercalcemia associated with mutation in the human
RT Ca(2+)-sensing receptor gene.";
RL J. Clin. Endocrinol. Metab. 80:2594-2598(1995).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 643-908.
RX PubMed=8613532; DOI=10.1172/jci118501;
RA Bikle D.D., Ratnam A., Mauro T., Harris J., Pillai S.;
RT "Changes in calcium responsiveness and handling during keratinocyte
RT differentiation. Potential role of the calcium receptor.";
RL J. Clin. Invest. 97:1085-1093(1996).
RN [9]
RP INTERACTION WITH VCP AND RNF19A, GLYCOSYLATION, AND UBIQUITINATION.
RX PubMed=16513638; DOI=10.1074/jbc.m513552200;
RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.;
RT "Calcium-sensing receptor ubiquitination and degradation mediated by the E3
RT ubiquitin ligase dorfin.";
RL J. Biol. Chem. 281:11610-11617(2006).
RN [10]
RP DOMAIN.
RX PubMed=17360426; DOI=10.1073/pnas.0611577104;
RA Muto T., Tsuchiya D., Morikawa K., Jingami H.;
RT "Structures of the extracellular regions of the group II/III metabotropic
RT glutamate receptors.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:3759-3764(2007).
RN [11]
RP SUBCELLULAR LOCATION, AND GLYCOSYLATION.
RX PubMed=20861236; DOI=10.1210/en.2010-0422;
RA Zhuang X., Adipietro K.A., Datta S., Northup J.K., Ray K.;
RT "Rab1 small GTP-binding protein regulates cell surface trafficking of the
RT human calcium-sensing receptor.";
RL Endocrinology 151:5114-5123(2010).
RN [12]
RP ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-482.
RX PubMed=26290606; DOI=10.1124/mol.115.098392;
RA Alexander S.T., Hunter T., Walter S., Dong J., Maclean D., Baruch A.,
RA Subramanian R., Tomlinson J.;
RT "Critical cysteine residues in both the calcium-sensing receptor and the
RT allosteric activator AMG 416 underlie the mechanism of action.";
RL Mol. Pharmacol. 88:853-865(2015).
RN [13] {ECO:0007744|PDB:5K5S, ECO:0007744|PDB:5K5T}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 20-607 IN COMPLEX WITH CALCIUM;
RP PHOSPHATE AND SULFATE ANIONS AND TRYPTOPHAN, FUNCTION, ACTIVITY REGULATION,
RP DOMAIN, DISULFIDE BONDS, GLYCOSYLATION AT ASN-261; ASN-287; ASN-446;
RP ASN-468; ASN-488; ASN-541 AND ASN-594, MUTAGENESIS OF ARG-69; ASN-102;
RP THR-145; SER-147; SER-170; TYR-218; SER-417 AND TRP-458, CHARACTERIZATION
RP OF VARIANTS NSHPT ILE-100; LEU-227 AND LYS-551, AND CHARACTERIZATION OF
RP VARIANTS HHC1 HIS-66; MET-81; PRO-159; GLY-172; GLY-215; LYS-297 AND
RP GLU-557.
RX PubMed=27434672; DOI=10.7554/elife.13662;
RA Geng Y., Mosyak L., Kurinov I., Zuo H., Sturchler E., Cheng T.C.,
RA Subramanyam P., Brown A.P., Brennan S.C., Mun H.C., Bush M., Chen Y.,
RA Nguyen T.X., Cao B., Chang D.D., Quick M., Conigrave A.D., Colecraft H.M.,
RA McDonald P., Fan Q.R.;
RT "Structural mechanism of ligand activation in human calcium-sensing
RT receptor.";
RL Elife 5:0-0(2016).
RN [14] {ECO:0007744|PDB:5FBH, ECO:0007744|PDB:5FBK}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 20-541 IN COMPLEX WITH MAGNESIUM
RP AND TRYPTOPHAN, FUNCTION, ACTIVITY REGULATION, DOMAIN, DISULFIDE BONDS, AND
RP MUTAGENESIS OF GLU-297.
RX PubMed=27386547; DOI=10.1126/sciadv.1600241;
RA Zhang C., Zhang T., Zou J., Miller C.L., Gorkhali R., Yang J.Y.,
RA Schilmiller A., Wang S., Huang K., Brown E.M., Moremen K.W., Hu J.,
RA Yang J.J.;
RT "Structural basis for regulation of human calcium-sensing receptor by
RT magnesium ions and an unexpected tryptophan derivative co-agonist.";
RL Sci. Adv. 2:E1600241-E1600241(2016).
RN [15]
RP VARIANTS HHC1 GLN-185; LYS-297 AND TRP-795.
RX PubMed=7916660; DOI=10.1016/0092-8674(93)90617-y;
RA Pollak M.R., Brown E.M., Chou Y.-H.W., Hebert S.C., Marx S.J.,
RA Steinmann B., Levi T., Seidman C.E., Seidman J.G.;
RT "Mutations in the human Ca(2+)-sensing receptor gene cause familial
RT hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.";
RL Cell 75:1297-1303(1993).
RN [16]
RP VARIANT HYPOC1 ALA-127.
RX PubMed=7874174; DOI=10.1038/ng1194-303;
RA Pollak M.R., Brown E.M., Estep H.L., McLaine P.N., Kifor O., Park J.,
RA Hebert S.C., Seidman C.E., Seidman J.G.;
RT "Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene
RT mutation.";
RL Nat. Genet. 8:303-307(1994).
RN [17]
RP VARIANTS HHC1 MET-62; CYS-66; MET-138; GLU-143 AND GLN-227.
RX PubMed=7726161;
RA Chou Y.-H.W., Pollak M.R., Brandi M.L., Toss G., Arnqvist H.,
RA Atkinson A.B., Papapoulos S.E., Marx S., Brown E.M., Seidman J.G.,
RA Seidman C.E.;
RT "Mutations in the human Ca(2+)-sensing-receptor gene that cause familial
RT hypocalciuric hypercalcemia.";
RL Am. J. Hum. Genet. 56:1075-1079(1995).
RN [18]
RP VARIANTS NSHPT LEU-227 AND TYR-582.
RX PubMed=8675635; DOI=10.1172/jci118335;
RA Pearce S.H.S., Trump D., Wooding C., Besser G.M., Chew S.L., Grant D.B.,
RA Heath D.A., Hughes I.A., Paterson C.R., Whyte M.P., Thakker R.V.;
RT "Calcium-sensing receptor mutations in familial benign hypercalcemia and
RT neonatal hyperparathyroidism.";
RL J. Clin. Invest. 96:2683-2692(1995).
RN [19]
RP VARIANT FIH MET-151.
RX PubMed=8698326; DOI=10.1007/s004390050174;
RA Lovlie R., Eiken H.G., Sorheim J.I., Boman H.;
RT "The Ca(2+)-sensing receptor gene (PCAR1) mutation T151M in isolated
RT autosomal dominant hypoparathyroidism.";
RL Hum. Genet. 98:129-133(1996).
RN [20]
RP VARIANTS HYPOC1 THR-116; HIS-681 AND SER-806, AND VARIANT SER-851.
RX PubMed=8733126; DOI=10.1093/hmg/5.5.601;
RA Baron J., Winer K.K., Yanovski J.A., Cunningham A.W., Laue L.,
RA Zimmerman D., Cutler G.B. Jr.;
RT "Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and
RT sporadic hypoparathyroidism.";
RL Hum. Mol. Genet. 5:601-606(1996).
RN [21]
RP VARIANTS HHC1 MET-62; CYS-66; MET-138; GLU-143; GLN-185; LYS-297 AND
RP TRP-795, VARIANT HYPOC1 ALA-127, FUNCTION, SUBCELLULAR LOCATION,
RP GLYCOSYLATION, CHARACTERIZATION OF VARIANTS HHC1 MET-62; CYS-66; MET-138;
RP GLU-143; GLN-185; LYS-297 AND TRP-795, AND CHARACTERIZATION OF VARIANT
RP HYPOC1 ALA-127.
RX PubMed=8702647; DOI=10.1074/jbc.271.32.19537;
RA Bai M., Quinn S., Trivedi S., Kifor O., Pearce S.H.S., Pollak M.R.,
RA Krapcho K., Hebert S.C., Brown E.M.;
RT "Expression and characterization of inactivating and activating mutations
RT in the human Ca2+o-sensing receptor.";
RL J. Biol. Chem. 271:19537-19545(1996).
RN [22]
RP VARIANTS HHC1 PRO-53; LEU-55; GLN-185; GLY-215; TYR-657 AND ARG-748,
RP VARIANTS SER-986; GLY-990 AND GLN-1011, AND CHARACTERIZATION OF VARIANTS
RP HHC1 PRO-53; LEU-55 AND GLY-215.
RX PubMed=8636323; DOI=10.1210/jcem.81.4.8636323;
RA Heath H. III, Odelberg S., Jackson C.E., Teh B.T., Hayward N., Larsson C.,
RA Buist N.R., Krapcho K.J., Hung B.C., Capuano I.V., Garrett J.E.,
RA Leppert M.F.;
RT "Clustered inactivating mutations and benign polymorphisms of the calcium
RT receptor gene in familial benign hypocalciuric hypercalcemia suggest
RT receptor functional domains.";
RL J. Clin. Endocrinol. Metab. 81:1312-1317(1996).
RN [23]
RP VARIANTS HHC1 LEU-55; ASP-178; SER-221 AND ILE-817, VARIANTS HYPOC1
RP LEU-128; MET-151 AND LYS-191, VARIANT NSHPT LEU-227, CHARACTERIZATION OF
RP VARIANTS HHC1 LEU-55; ASP-178; SER-221 AND ILE-817, FUNCTION,
RP CHARACTERIZATION OF VARIANTS HYPOC1 LEU-128; MET-151 AND LYS-191, AND
RP CHARACTERIZATION OF VARIANT NSHPT LEU-227.
RX PubMed=8878438; DOI=10.1172/jci118987;
RA Pearce S.H.S., Bai M., Quinn S.J., Kifor O., Brown E.M., Thakker R.V.;
RT "Functional characterization of calcium-sensing receptor mutations
RT expressed in human embryonic kidney cells.";
RL J. Clin. Invest. 98:1860-1866(1996).
RN [24]
RP VARIANT HHC1 ARG-174.
RX PubMed=9298824;
RX DOI=10.1002/(sici)1098-1004(1997)10:3<233::aid-humu9>3.0.co;2-j;
RA Ward B.K., Stuckey B.G.A., Gutteridge D.H., Laing N.G., Pullan P.T.,
RA Ratajczak T.;
RT "A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with
RT familial hypocalciuric hypercalcemia.";
RL Hum. Mutat. 10:233-235(1997).
RN [25]
RP VARIANTS HYPOC1 LYS-118; ARG-773 AND SER-806, AND CHARACTERIZATION OF
RP VARIANTS HYPOC1 LYS-118; ARG-773 AND SER-806.
RX PubMed=9253358; DOI=10.1210/jcem.82.8.4166;
RA De Luca F., Ray K., Mancilla E.E., Fan G.-F., Winer K.K., Gore P.,
RA Spiegel A.M., Baron J.;
RT "Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations
RT of the Ca(2+)-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 82:2710-2715(1997).
RN [26]
RP VARIANT NSHPT GLU-670.
RX PubMed=9253359; DOI=10.1210/jcem.82.8.4135;
RA Kobayashi M., Tanaka H., Tsuzuki K., Tsuyuki M., Igaki H., Ichinose Y.,
RA Aya K., Nishioka N., Seino Y.;
RT "Two novel missense mutations in calcium-sensing receptor gene associated
RT with neonatal severe hyperparathyroidism.";
RL J. Clin. Endocrinol. Metab. 82:2716-2719(1997).
RN [27]
RP VARIANT HYPOC1 CYS-788, AND CHARACTERIZATION OF VARIANT HYPOC1 CYS-788.
RX PubMed=9661634; DOI=10.1210/jcem.83.7.4920;
RA Watanabe T., Bai M., Lane C.R., Matsumoto S., Minamitani K., Minagawa M.,
RA Niimi H., Brown E.M., Yasuda T.;
RT "Familial hypoparathyroidism: identification of a novel gain of function
RT mutation in transmembrane domain 5 of the calcium-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 83:2497-2502(1998).
RN [28]
RP VARIANT ARG-27, CHARACTERIZATION OF VARIANT ARG-27, AND INVOLVEMENT IN
RP PRIMARY HYPERPARATHYROIDISM.
RX PubMed=10468915; DOI=10.1046/j.1365-2265.1999.00729.x;
RA Chikatsu N., Fukumoto S., Suzawa M., Tanaka Y., Takeuchi Y., Takeda S.,
RA Tamura Y., Matsumoto T., Fujita T.;
RT "An adult patient with severe hypercalcaemia and hypocalciuria due to a
RT novel homozygous inactivating mutation of calcium-sensing receptor.";
RL Clin. Endocrinol. (Oxf.) 50:537-543(1999).
RN [29]
RP VARIANT HYPOC1 ASN-47, AND CHARACTERIZATION OF VARIANT HYPOC1 ASN-47.
RX PubMed=9920108; DOI=10.1210/jcem.84.1.5385;
RA Okazaki R., Chikatsu N., Nakatsu M., Takeuchi Y., Ajima M., Miki J.,
RA Fujita T., Arai M., Totsuka Y., Tanaka K., Fukumoto S.;
RT "A novel activating mutation in calcium-sensing receptor gene associated
RT with a family of autosomal dominant hypocalcemia.";
RL J. Clin. Endocrinol. Metab. 84:363-366(1999).
RN [30]
RP VARIANT HYPOC1 VAL-616, AND CHARACTERIZATION OF VARIANT HYPOC1 VAL-616.
RX PubMed=10487661; DOI=10.1210/jcem.84.9.5977;
RA Stock J.L., Brown R.S., Baron J., Coderre J.A., Mancilla E., De Luca F.,
RA Ray K., Mericq M.V.;
RT "Autosomal dominant hypoparathyroidism associated with short stature and
RT premature osteoarthritis.";
RL J. Clin. Endocrinol. Metab. 84:3036-3040(1999).
RN [31]
RP VARIANT SER-986, AND ASSOCIATION WITH SERUM LEVEL OF CALCIUM.
RX PubMed=10023897; DOI=10.1016/s0140-6736(98)06434-4;
RA Cole D.E.C., Peltekova V.D., Rubin L.A., Hawker G.A., Vieth R., Liew C.C.,
RA Hwang D.M., Evrovski J., Hendy G.N.;
RT "A986S polymorphism of the calcium-sensing receptor and circulating calcium
RT concentrations.";
RL Lancet 353:112-115(1999).
RN [32]
RP VARIANT HYPERCALCIURIC HYPERCALCEMIA LEU-881, AND CHARACTERIZATION OF
RP VARIANT HYPERCALCIURIC HYPERCALCEMIA LEU-881.
RX PubMed=10843194; DOI=10.1210/jcem.85.5.6477;
RA Carling T., Szabo E., Bai M., Ridefelt P., Westin G., Gustavsson P.,
RA Trivedi S., Hellman P., Brown E.M., Dahl N., Rastad J.;
RT "Familial hypercalcemia and hypercalciuria caused by a novel mutation in
RT the cytoplasmic tail of the calcium receptor.";
RL J. Clin. Endocrinol. Metab. 85:2042-2047(2000).
RN [33]
RP VARIANT HHC1 GLU-557.
RX PubMed=11762699; DOI=10.1385/endo:15:3:277;
RA Nakayama T., Minato M., Nakagawa M., Soma M., Tobe H., Aoi N., Kosuge K.,
RA Sato M., Ozawa Y., Kanmatsuse K., Kokubun S.;
RT "A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric
RT hypercalcemia.";
RL Endocrine 15:277-282(2001).
RN [34]
RP VARIANT SER-986, ASSOCIATION WITH SERUM LEVEL OF CALCIUM, AND PREDISPOSING
RP FACTOR IN DISORDERS OF BONE AND MINERAL METABOLISM.
RX PubMed=11161843; DOI=10.1006/mgme.2000.3126;
RA Cole D.E.C., Vieth R., Trang H.M., Wong B.Y.-L., Hendy G.N., Rubin L.A.;
RT "Association between total serum calcium and the A986S polymorphism of the
RT calcium-sensing receptor gene.";
RL Mol. Genet. Metab. 72:168-174(2001).
RN [35]
RP VARIANT HYPOC1 PHE-820, CHARACTERIZATION OF VARIANT HYPOC1 PHE-820, AND
RP VARIANT GLY-990.
RX PubMed=12050233; DOI=10.1210/jcem.87.6.8531;
RA Nagase T., Murakami T., Tsukada T., Kitamura R., Chikatsu N., Takeo H.,
RA Takata N., Yasuda H., Fukumoto S., Tanaka Y., Nagata N., Yamaguchi K.,
RA Akatsu T., Yamamoto M.;
RT "A family of autosomal dominant hypocalcemia with a positive correlation
RT between serum calcium and magnesium: identification of a novel gain of
RT function mutation (Ser(820)Phe) in the calcium-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 87:2681-2687(2002).
RN [36]
RP VARIANTS HYPOC1 PRO-125 AND GLU-843, AND CHARACTERIZATION OF VARIANTS
RP HYPOC1 PRO-125 AND GLU-843.
RX PubMed=12107202; DOI=10.1210/jcem.87.7.8639;
RA Sato K., Hasegawa Y., Nakae J., Nanao K., Takahashi I., Tajima T.,
RA Shinohara N., Fujieda K.;
RT "Hydrochlorothiazide effectively reduces urinary calcium excretion in two
RT Japanese patients with gain-of-function mutations of the calcium-sensing
RT receptor gene.";
RL J. Clin. Endocrinol. Metab. 87:3068-3073(2002).
RN [37]
RP VARIANTS HYPOC1 TRP-131 AND GLU-843.
RX PubMed=12241879; DOI=10.1016/s0140-6736(02)09842-2;
RA Watanabe S., Fukumoto S., Chang H., Takeuchi Y., Hasegawa Y., Okazaki R.,
RA Chikatsu N., Fujita T.;
RT "Association between activating mutations of calcium-sensing receptor and
RT Bartter's syndrome.";
RL Lancet 360:692-694(2002).
RN [38]
RP VARIANT HYPOC1 LYS-604, AND CHARACTERIZATION OF VARIANT HYPOC1 LYS-604.
RX PubMed=12574188; DOI=10.1210/jc.2002-020081;
RA Tan Y.M., Cardinal J., Franks A.H., Mun H.-C., Lewis N., Harris L.B.,
RA Prins J.B., Conigrave A.D.;
RT "Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in
RT the cysteine-rich domain of the calcium-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 88:605-610(2003).
RN [39]
RP VARIANT HYPOC1 LEU-788, AND CHARACTERIZATION OF VARIANT HYPOC1 LEU-788.
RX PubMed=12915654; DOI=10.1210/jc.2003-030409;
RA Hendy G.N., Minutti C., Canaff L., Pidasheva S., Yang B., Nouhi Z.,
RA Zimmerman D., Wei C., Cole D.E.C.;
RT "Recurrent familial hypocalcemia due to germline mosaicism for an
RT activating mutation of the calcium-sensing receptor gene.";
RL J. Clin. Endocrinol. Metab. 88:3674-3681(2003).
RN [40]
RP VARIANTS SER-986; GLY-990 AND GLN-1011, AND ASSOCIATION WITH SERUM LEVEL OF
RP CALCIUM.
RX PubMed=15531522; DOI=10.1210/jc.2004-0129;
RA Scillitani A., Guarnieri V., De Geronimo S., Muscarella L.A., Battista C.,
RA D'Agruma L., Bertoldo F., Florio C., Minisola S., Hendy G.N., Cole D.E.C.;
RT "Blood ionized calcium is associated with clustered polymorphisms in the
RT carboxyl-terminal tail of the calcium-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 89:5634-5638(2004).
RN [41]
RP VARIANT HHC1 PRO-13, AND CHARACTERIZATION OF VARIANT HHC1 PRO-13.
RX PubMed=15579740; DOI=10.1210/jc.2004-1046;
RA Miyashiro K., Kunii I., Manna T.D., de Menezes Filho H.C., Damiani D.,
RA Setian N., Hauache O.M.;
RT "Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel
RT inactivating mutation of the calcium-sensing receptor.";
RL J. Clin. Endocrinol. Metab. 89:5936-5941(2004).
RN [42]
RP VARIANTS NSHPT ILE-100; LYS-336 DEL; PRO-650 AND MET-689, AND VARIANTS
RP SER-986; GLY-990 AND GLN-1011.
RX PubMed=14985373; DOI=10.1136/jmg.2003.016725;
RA Warner J., Epstein M., Sweet A., Singh D., Burgess J., Stranks S., Hill P.,
RA Perry-Keene D., Learoyd D., Robinson B., Birdsey P., Mackenzie E.,
RA Teh B.T., Prins J.B., Cardinal J.;
RT "Genetic testing in familial isolated hyperparathyroidism: unexpected
RT results and their implications.";
RL J. Med. Genet. 41:155-160(2004).
RN [43]
RP VARIANT HYPOC1 LYS-767, AND VARIANT GLY-990.
RX PubMed=15551332; DOI=10.1002/ajmg.a.30403;
RA Uckun-Kitapci A., Underwood L.E., Zhang J., Moats-Staats B.;
RT "A novel mutation (E767K) in the second extracellular loop of the calcium
RT sensing receptor in a family with autosomal dominant hypocalcemia.";
RL Am. J. Med. Genet. A 132:125-129(2005).
RN [44]
RP VARIANTS HHC1 SER-11 AND PRO-13, VARIANT ALA-14, CHARACTERIZATION OF
RP VARIANTS HHC1 SER-11 AND PRO-13, AND CHARACTERIZATION OF VARIANT ALA-14.
RX PubMed=15879434; DOI=10.1093/hmg/ddi176;
RA Pidasheva S., Canaff L., Simonds W.F., Marx S.J., Hendy G.N.;
RT "Impaired cotranslational processing of the calcium-sensing receptor due to
RT signal peptide missense mutations in familial hypocalciuric
RT hypercalcemia.";
RL Hum. Mol. Genet. 14:1679-1690(2005).
RN [45]
RP VARIANT HHC1 GLN-227, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT
RP NSHPT LEU-227, AND CHARACTERIZATION OF VARIANT HHC1 GLN-227.
RX PubMed=15572418; DOI=10.1210/jc.2004-1791;
RA Wystrychowski A., Pidasheva S., Canaff L., Chudek J., Kokot F., Wiecek A.,
RA Hendy G.N.;
RT "Functional characterization of calcium-sensing receptor codon 227
RT mutations presenting as either familial (benign) hypocalciuric
RT hypercalcemia or neonatal hyperparathyroidism.";
RL J. Clin. Endocrinol. Metab. 90:864-870(2005).
RN [46]
RP VARIANT HHC1 GLN-465, CHARACTERIZATION OF VARIANT HHC1 GLN-465, AND VARIANT
RP SER-986.
RX PubMed=16598859; DOI=10.1016/j.bbrc.2006.02.018;
RA Leech C., Lohse P., Stanojevic V., Lechner A., Goeke B., Spitzweg C.;
RT "Identification of a novel inactivating R465Q mutation of the calcium-
RT sensing receptor.";
RL Biochem. Biophys. Res. Commun. 342:996-1002(2006).
RN [47]
RP VARIANTS HHC1 CYS-66; HIS-66 AND 583-ASN--SER-1078 DEL, SUBCELLULAR
RP LOCATION, SUBUNIT, GLYCOSYLATION, AND CHARACTERIZATION OF VARIANTS CYS-66;
RP HIS-66 AND 583-ASN--SER-1078 DEL.
RX PubMed=16740594; DOI=10.1093/hmg/ddl145;
RA Pidasheva S., Grant M., Canaff L., Ercan O., Kumar U., Hendy G.N.;
RT "Calcium-sensing receptor dimerizes in the endoplasmic reticulum:
RT biochemical and biophysical characterization of CASR mutants retained
RT intracellularly.";
RL Hum. Mol. Genet. 15:2200-2209(2006).
RN [48]
RP VARIANT HYPOC1 GLN-727, AND CHARACTERIZATION OF VARIANT HYPOC1 GLN-727.
RX PubMed=16608894; DOI=10.1210/jc.2005-2605;
RA Mittelman S.D., Hendy G.N., Fefferman R.A., Canaff L., Mosesova I.,
RA Cole D.E., Burkett L., Geffner M.E.;
RT "A hypocalcemic child with a novel activating mutation of the calcium-
RT sensing receptor gene: successful treatment with recombinant human
RT parathyroid hormone.";
RL J. Clin. Endocrinol. Metab. 91:2474-2479(2006).
RN [49]
RP VARIANT HHC1 CYS-180, AND CHARACTERIZATION OF VARIANT HHC1 CYS-180.
RX PubMed=17473068; DOI=10.1210/jc.2007-0123;
RA Zajickova K., Vrbikova J., Canaff L., Pawelek P.D., Goltzman D.,
RA Hendy G.N.;
RT "Identification and functional characterization of a novel mutation in the
RT calcium-sensing receptor gene in familial hypocalciuric hypercalcemia:
RT modulation of clinical severity by vitamin D status.";
RL J. Clin. Endocrinol. Metab. 92:2616-2623(2007).
RN [50]
RP VARIANT NSHPT LYS-551, VARIANT SER-986, FUNCTION, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANT NSHPT LYS-551.
RX PubMed=17555508; DOI=10.1111/j.1365-2265.2007.02896.x;
RA Toke J., Czirjak G., Patocs A., Enyedi B., Gergics P., Csakvary V.,
RA Enyedi P., Toth M.;
RT "Neonatal severe hyperparathyroidism associated with a novel de novo
RT heterozygous R551K inactivating mutation and a heterozygous A986S
RT polymorphism of the calcium-sensing receptor gene.";
RL Clin. Endocrinol. (Oxf.) 67:385-392(2007).
RN [51]
RP VARIANTS HHC1 ARG-21; ASN-171; GLN-221; THR-225; PHE-271; ARG-397; ARG-509;
RP ARG-553; VAL-555; TYR-562; PHE-582; TYR-582; ASP-623; ARG-670; PHE-728;
RP ARG-742 AND TRP-886, AND VARIANTS LYS-250; SER-986; GLY-990 AND GLN-1011.
RX PubMed=17698911; DOI=10.1210/jc.2007-0322;
RA Nissen P.H., Christensen S.E., Heickendorff L., Brixen K., Mosekilde L.;
RT "Molecular genetic analysis of the calcium sensing receptor gene in
RT patients clinically suspected to have familial hypocalciuric hypercalcemia:
RT phenotypic variation and mutation spectrum in a Danish population.";
RL J. Clin. Endocrinol. Metab. 92:4373-4379(2007).
RN [52]
RP VARIANTS EIG8 ALA-354; VAL-686; GLN-898; VAL-988 AND GLY-988, VARIANTS
RP SER-986 AND GLY-990, AND TISSUE SPECIFICITY.
RX PubMed=18756473; DOI=10.1002/ana.21428;
RA Kapoor A., Satishchandra P., Ratnapriya R., Reddy R., Kadandale J.,
RA Shankar S.K., Anand A.;
RT "An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense
RT mutations in the extracellular calcium sensing receptor gene.";
RL Ann. Neurol. 64:158-167(2008).
RN [53]
RP VARIANT HHC1 ARG-459, VARIANTS SER-986 AND GLN-1011, FUNCTION, AND
RP CHARACTERIZATION OF VARIANT HHC1 ARG-459.
RX PubMed=19789209; DOI=10.1210/jc.2008-2484;
RA Lietman S.A., Tenenbaum-Rakover Y., Jap T.S., Yi-Chi W., De-Ming Y.,
RA Ding C., Kussiny N., Levine M.A.;
RT "A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing
RT receptor gene associated with apparent autosomal recessive inheritance of
RT familial hypocalciuric hypercalcemia.";
RL J. Clin. Endocrinol. Metab. 94:4372-4379(2009).
RN [54]
RP VARIANTS HHC1 SER-42; LEU-55; HIS-66; MET-81; MET-138; ARG-143; ARG-158;
RP GLY-166; TRP-220; ARG-549; TYR-562; GLY-565; TYR-582; 583-ASN--SER-1078
RP DEL; TYR-661; HIS-680; ILE-761 DEL AND TRP-795, AND VARIANTS HYPOC1
RP LYS-118; PHE-125; ARG-129; LYS-228; LYS-604; ILE-802; SER-830; LEU-832 AND
RP SER-832.
RX PubMed=19179454; DOI=10.1677/jme-08-0164;
RA Cole D.E., Yun F.H., Wong B.Y., Shuen A.Y., Booth R.A., Scillitani A.,
RA Pidasheva S., Zhou X., Canaff L., Hendy G.N.;
RT "Calcium-sensing receptor mutations and denaturing high performance liquid
RT chromatography.";
RL J. Mol. Endocrinol. 42:331-339(2009).
RN [55]
RP VARIANT THR-339, CHARACTERIZATION OF VARIANT THR-339, AND INVOLVEMENT IN
RP PRIMARY HYPERPARATHYROIDISM.
RX PubMed=20846291; DOI=10.1111/j.1365-2265.2010.03870.x;
RA Hannan F.M., Nesbit M.A., Christie P.T., Lissens W., Van der Schueren B.,
RA Bex M., Bouillon R., Thakker R.V.;
RT "A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is
RT associated with isolated primary hyperparathyroidism: correlation between
RT location of mutations and severity of hypercalcaemia.";
RL Clin. Endocrinol. (Oxf.) 73:715-722(2010).
RN [56]
RP VARIANT HHC1 ILE-550, FUNCTION, AND CHARACTERIZATION OF VARIANT HHC1
RP ILE-550.
RX PubMed=21566075; DOI=10.1530/eje-11-0141;
RA Al-Salameh A., Cetani F., Pardi E., Vulpoi C., Pierre P., de Calan L.,
RA Guyetant S., Jeunemaitre X., Lecomte P.;
RT "A novel mutation in the calcium-sensing receptor in a French family with
RT familial hypocalciuric hypercalcaemia.";
RL Eur. J. Endocrinol. 165:359-363(2011).
RN [57]
RP VARIANTS HHC1 PRO-159 AND TRP-795, FUNCTION, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANTS HHC1 PRO-159 AND TRP-795.
RX PubMed=22114145; DOI=10.1126/scisignal.2002208;
RA Grant M.P., Stepanchick A., Cavanaugh A., Breitwieser G.E.;
RT "Agonist-driven maturation and plasma membrane insertion of calcium-sensing
RT receptors dynamically control signal amplitude.";
RL Sci. Signal. 4:RA78-RA78(2011).
RN [58]
RP VARIANT HHC1 MET-697.
RX PubMed=21643651; DOI=10.1007/s00431-011-1504-8;
RA Aparicio Lopez C., Anton-Martin P., Gil-Fournier B., Ramiro-Leon S.,
RA Perez-Nanclares G., Perez de Nanclares G., Martinez Menendez B.,
RA Castano L.;
RT "Familial hypocalciuric hypercalcemia: new mutation in the CASR gene
RT converting valine 697 to methionine.";
RL Eur. J. Pediatr. 171:147-150(2012).
RN [59]
RP VARIANTS HHC1 THR-110 AND GLY-172, VARIANTS HYPOC1 CYS-122; HIS-569 AND
RP THR-839, FUNCTION, CHARACTERIZATION OF VARIANTS HHC1 THR-110 AND GLY-172,
RP AND CHARACTERIZATION OF VARIANTS HYPOC1 CYS-122; HIS-569 AND THR-839.
RX PubMed=23966241; DOI=10.1210/jc.2013-1974;
RA Nakamura A., Hotsubo T., Kobayashi K., Mochizuki H., Ishizu K., Tajima T.;
RT "Loss-of-function and gain-of-function mutations of calcium-sensing
RT receptor: functional analysis and the effect of allosteric modulators NPS
RT R-568 and NPS 2143.";
RL J. Clin. Endocrinol. Metab. 98:E1692-E1701(2013).
RN [60]
RP VARIANT HHC1 SER-802, AND VARIANT HYPOC1 ILE-802.
RX PubMed=23169696; DOI=10.1530/eje-12-0714;
RA Lia-Baldini A.S., Magdelaine C., Nizou A., Airault C., Salles J.P.,
RA Moulin P., Delemer B., Aitouares M., Funalot B., Sturtz F.,
RA Lienhardt-Roussie A.;
RT "Two novel mutations of the calcium-sensing receptor gene affecting the
RT same amino acid position lead to opposite phenotypes and reveal the
RT importance of p.N802 on receptor activity.";
RL Eur. J. Endocrinol. 168:K27-K34(2013).
RN [61]
RP VARIANT HHC1 MET-972, FUNCTION, AND CHARACTERIZATION OF VARIANT HHC1
RP MET-972.
RX PubMed=25292184; DOI=10.1186/1472-6823-14-81;
RA Mastromatteo E., Lamacchia O., Campo M.R., Conserva A., Baorda F.,
RA Cinque L., Guarnieri V., Scillitani A., Cignarelli M.;
RT "A novel mutation in calcium-sensing receptor gene associated to
RT hypercalcemia and hypercalciuria.";
RL BMC Endocr. Disord. 14:81-81(2014).
RN [62]
RP VARIANTS HHC1 VAL-707 AND SER-774, FUNCTION, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANTS HHC1 VAL-707 AND SER-774.
RX PubMed=25104082; DOI=10.1093/ndt/gfu065;
RA Stratta P., Merlotti G., Musetti C., Quaglia M., Pagani A., Izzo C.,
RA Radin E., Airoldi A., Baorda F., Palladino T., Leone M.P., Guarnieri V.;
RT "Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric
RT patients as differential diagnosis from primary hyperparathyroidism:
RT detection of two novel inactivating mutations in an Italian population.";
RL Nephrol. Dial. Transplant. 29:1902-1909(2014).
RN [63]
RP VARIANT HHC1 TRP-571, FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION
RP OF VARIANT HHC1 TRP-571.
RX PubMed=26386835; DOI=10.1007/s00774-015-0713-z;
RA Kim E.S., Kim S.Y., Lee J.Y., Han J.H., Sohn T.S., Son H.S., Moon S.D.;
RT "Identification and functional analysis of a novel CaSR mutation in a
RT family with familial hypocalciuric hypercalcemia.";
RL J. Bone Miner. Metab. 34:662-667(2016).
RN [64]
RP VARIANT HYPOC1 LEU-136, FUNCTION, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANT HYPOC1 LEU-136.
RX PubMed=25766501; DOI=10.1016/j.mce.2015.02.021;
RA Baran N., ter Braak M., Saffrich R., Woelfle J., Schmitz U.;
RT "Novel activating mutation of human calcium-sensing receptor in a family
RT with autosomal dominant hypocalcaemia.";
RL Mol. Cell. Endocrinol. 407:18-25(2015).
RN [65]
RP VARIANTS HYPOC1 LEU-221; ARG-681 AND GLN-727, FUNCTION, SUBCELLULAR
RP LOCATION, AND CHARACTERIZATION OF VARIANTS HYPOC1 ARG-681 AND GLN-727.
RX PubMed=22789683; DOI=10.1016/j.ymgme.2012.06.012;
RA Guarnieri V., Valentina D'Elia A., Baorda F., Pazienza V., Benegiamo G.,
RA Stanziale P., Copetti M., Battista C., Grimaldi F., Damante G.,
RA Pellegrini F., D'Agruma L., Zelante L., Carella M., Scillitani A.;
RT "CASR gene activating mutations in two families with autosomal dominant
RT hypocalcemia.";
RL Mol. Genet. Metab. 107:548-552(2012).
CC -!- FUNCTION: G-protein-coupled receptor that senses changes in the
CC extracellular concentration of calcium ions and plays a key role in
CC maintaining calcium homeostasis (PubMed:7759551, PubMed:8702647,
CC PubMed:8636323, PubMed:8878438, PubMed:17555508, PubMed:19789209,
CC PubMed:21566075, PubMed:22114145, PubMed:23966241, PubMed:25292184,
CC PubMed:25104082, PubMed:26386835, PubMed:25766501, PubMed:22789683).
CC Senses fluctuations in the circulating calcium concentration and
CC modulates the production of parathyroid hormone (PTH) in parathyroid
CC glands (By similarity). The activity of this receptor is mediated by a
CC G-protein that activates a phosphatidylinositol-calcium second
CC messenger system (PubMed:7759551). The G-protein-coupled receptor
CC activity is activated by a co-agonist mechanism: aromatic amino acids,
CC such as Trp or Phe, act concertedly with divalent cations, such as
CC calcium or magnesium, to achieve full receptor activation
CC (PubMed:27434672, PubMed:27386547). {ECO:0000250|UniProtKB:Q9QY96,
CC ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:19789209,
CC ECO:0000269|PubMed:21566075, ECO:0000269|PubMed:22114145,
CC ECO:0000269|PubMed:22789683, ECO:0000269|PubMed:23966241,
CC ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184,
CC ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:26386835,
CC ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672,
CC ECO:0000269|PubMed:7759551, ECO:0000269|PubMed:8636323,
CC ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438}.
CC -!- ACTIVITY REGULATION: In resting state, adopts an open conformation,
CC anion-binding promoting the inactive configuration (PubMed:27434672).
CC Upon aromatic amino acid-binding, the groove in the extracellular venus
CC flytrap module is closed, thereby inducing the formation of a novel
CC homodimer interface between subunits (PubMed:27434672,
CC PubMed:27386547). Calcium ions stabilize the active state by enhancing
CC homodimer interactions between membrane-proximal domains to fully
CC activate the receptor (PubMed:27434672, PubMed:27386547). Activated by
CC AMG 416, a D-amino acid-containing peptide agonist that is being
CC evaluated for the treatment of secondary hyperparathyroidism in chronic
CC kidney disease patients receiving hemodialysis (PubMed:26290606). AMG
CC 416 agonist acts by forming a disulfide bond with Cys-482
CC (PubMed:26290606). {ECO:0000269|PubMed:26290606,
CC ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672}.
CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:27434672, PubMed:27386547,
CC PubMed:16740594). Interacts with VCP and RNF19A (PubMed:16513638).
CC Interacts with ARRB1 (By similarity). {ECO:0000250|UniProtKB:P48442,
CC ECO:0000269|PubMed:16513638, ECO:0000269|PubMed:16740594,
CC ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672}.
CC -!- INTERACTION:
CC P41180; Q15363: TMED2; NbExp=3; IntAct=EBI-4400127, EBI-998485;
CC P41180-1; P41180-1: CASR; NbExp=2; IntAct=EBI-27048496, EBI-27048496;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15572418,
CC ECO:0000269|PubMed:16740594, ECO:0000269|PubMed:17555508,
CC ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:20861236,
CC ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:22789683,
CC ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25766501,
CC ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:8702647}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:20861236}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P41180-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P41180-2; Sequence=VSP_002035;
CC -!- TISSUE SPECIFICITY: Expressed in the temporal lobe, frontal lobe,
CC parietal lobe, hippocampus, and cerebellum. Also found in kidney, lung,
CC liver, heart, skeletal muscle, placenta. {ECO:0000269|PubMed:18756473}.
CC -!- DOMAIN: The extracellular regions of the homodimer interact in a side-
CC by-side fashion while facing opposite directions (PubMed:27434672,
CC PubMed:27386547). Each extracellular region consists of three domains,
CC LB1 (ligand-binding 1), LB2 and CR (cysteine-rich) (PubMed:17360426).
CC The two lobe-shaped domains LB1 and LB2 form a venus flytrap module
CC (PubMed:27434672, PubMed:27386547). In the inactive configuration, the
CC venus flytrap modules of both protomers are in the open conformation
CC associated with the resting state (open-open) and the interdomain cleft
CC is empty (PubMed:27434672). In addition, each protomer contains three
CC anions, which reinforce the inactive conformation, and one calcium ion
CC (PubMed:27434672). In the active configuration, both protomers of
CC extracellular regions have the closed conformation associated with
CC agonist-binding (closed-closed) (PubMed:27434672, PubMed:27386547). The
CC ligand-binding cleft of each protomer is solely occupied by an aromatic
CC amino-acid (PubMed:27434672, PubMed:27386547). Calcium is bound at four
CC novel sites, including one at the homodimer interface (PubMed:27434672,
CC PubMed:27386547). Agonist-binding induces large conformational changes
CC within the extracellular region homodimer: first, the venus flytrap
CC module of each protomer undergoes domain closure (PubMed:27434672,
CC PubMed:27386547). Second, the LB2 regions of the two protomers approach
CC each other, resulting in an expansion of the homodimer interactions
CC involving LB2 domains (PubMed:27434672, PubMed:27386547). Third, the CR
CC regions of the two subunits interact to form a large homodimer
CC interface that is unique to the active state (PubMed:27434672,
CC PubMed:27386547). The CR regions are brought into close contact by the
CC motion involving LB2 since the two domains are rigidly associated
CC within each subunit (PubMed:27434672, PubMed:27386547).
CC {ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672,
CC ECO:0000303|PubMed:17360426}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:16513638,
CC ECO:0000269|PubMed:16740594, ECO:0000269|PubMed:20861236,
CC ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:8702647}.
CC -!- PTM: Ubiquitinated by RNF19A; which induces proteasomal degradation.
CC {ECO:0000269|PubMed:16513638}.
CC -!- DISEASE: Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980]: A
CC form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis
CC that is transmitted as an autosomal dominant trait with a high degree
CC of penetrance. It is characterized biochemically by lifelong elevation
CC of serum calcium concentrations and is associated with inappropriately
CC low urinary calcium excretion and a normal or mildly elevated
CC circulating parathyroid hormone level. Hypermagnesemia is typically
CC present. Affected individuals are usually asymptomatic and the disorder
CC is considered benign. However, chondrocalcinosis and pancreatitis occur
CC in some adults. {ECO:0000269|PubMed:11762699,
CC ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:15579740,
CC ECO:0000269|PubMed:15879434, ECO:0000269|PubMed:16598859,
CC ECO:0000269|PubMed:16740594, ECO:0000269|PubMed:17473068,
CC ECO:0000269|PubMed:17698911, ECO:0000269|PubMed:19179454,
CC ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:21566075,
CC ECO:0000269|PubMed:21643651, ECO:0000269|PubMed:22114145,
CC ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241,
CC ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184,
CC ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:27434672,
CC ECO:0000269|PubMed:7673400, ECO:0000269|PubMed:7726161,
CC ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:8636323,
CC ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438,
CC ECO:0000269|PubMed:9298824}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200]: A
CC disorder characterized by severe hypercalcemia, bone demineralization,
CC and failure to thrive usually manifesting in the first 6 months of
CC life. If untreated, NSHPT can be a devastating neurodevelopmental
CC disorder, which in some cases is lethal without parathyroidectomy.
CC {ECO:0000269|PubMed:14985373, ECO:0000269|PubMed:15572418,
CC ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:27434672,
CC ECO:0000269|PubMed:8675635, ECO:0000269|PubMed:8878438,
CC ECO:0000269|PubMed:9253359}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198]: A
CC disorder of mineral homeostasis characterized by blood calcium levels
CC below normal, and low or normal serum parathyroid hormone
CC concentrations. Disease manifestations include mild or asymptomatic
CC hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria
CC with nephrocalcinosis or kidney stones, and ectopic and basal ganglia
CC calcifications. Few patients manifest hypocalcemia and features of
CC Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic
CC alkalosis, hyperreninemia, and hyperaldosteronemia.
CC {ECO:0000269|PubMed:10487661, ECO:0000269|PubMed:12050233,
CC ECO:0000269|PubMed:12107202, ECO:0000269|PubMed:12241879,
CC ECO:0000269|PubMed:12574188, ECO:0000269|PubMed:12915654,
CC ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:16608894,
CC ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:22789683,
CC ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241,
CC ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:7874174,
CC ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8733126,
CC ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:8878438,
CC ECO:0000269|PubMed:9253358, ECO:0000269|PubMed:9661634,
CC ECO:0000269|PubMed:9920108}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899]: A
CC disorder characterized by recurring generalized seizures in the absence
CC of detectable brain lesions and/or metabolic abnormalities. Seizure
CC types are variable, but include myoclonic seizures, absence seizures,
CC febrile seizures, complex partial seizures, and generalized tonic-
CC clonic seizures. {ECO:0000269|PubMed:18756473}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 3 family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB29413.2; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/casr/";
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DR EMBL; X81086; CAA56990.1; -; Genomic_DNA.
DR EMBL; U20759; AAA86503.1; -; mRNA.
DR EMBL; U20760; AAA86504.1; -; mRNA.
DR EMBL; D50855; BAA09453.1; -; mRNA.
DR EMBL; S83176; AAB46873.1; -; mRNA.
DR EMBL; S79217; AAB35262.2; -; mRNA.
DR EMBL; S81755; AAD14370.1; -; mRNA.
DR EMBL; S68032; AAB29413.2; ALT_SEQ; Genomic_DNA.
DR EMBL; S68033; AAB29414.1; -; Genomic_DNA.
DR EMBL; S68036; AAB29415.1; -; Genomic_DNA.
DR EMBL; DQ088967; AAY68221.1; -; Genomic_DNA.
DR EMBL; BC104999; AAI05000.1; -; mRNA.
DR EMBL; BC112236; AAI12237.1; -; mRNA.
DR CCDS; CCDS3010.1; -. [P41180-1]
DR CCDS; CCDS54632.1; -. [P41180-2]
DR PIR; A56715; A56715.
DR PIR; B56715; B56715.
DR RefSeq; NP_000379.2; NM_000388.3. [P41180-1]
DR RefSeq; NP_001171536.1; NM_001178065.1. [P41180-2]
DR RefSeq; XP_006713852.1; XM_006713789.3. [P41180-1]
DR RefSeq; XP_016862813.1; XM_017007324.1. [P41180-1]
DR RefSeq; XP_016862814.1; XM_017007325.1. [P41180-1]
DR PDB; 5FBH; X-ray; 2.70 A; A/B=20-541.
DR PDB; 5FBK; X-ray; 2.10 A; A/B=20-541.
DR PDB; 5K5S; X-ray; 2.60 A; A/B=20-607.
DR PDB; 5K5T; X-ray; 3.10 A; A=20-607.
DR PDB; 7DTT; EM; 3.80 A; A/B=20-1078.
DR PDB; 7DTU; EM; 4.40 A; A/B=20-1078.
DR PDB; 7DTV; EM; 3.50 A; A/B=20-1078.
DR PDB; 7DTW; EM; 4.50 A; A/B=20-1078.
DR PDB; 7E6T; EM; 3.00 A; A/B=20-870.
DR PDB; 7E6U; EM; 6.00 A; A/C=20-870.
DR PDB; 7M3E; EM; 3.20 A; A/B=20-894.
DR PDB; 7M3F; EM; 2.80 A; A/B=20-894.
DR PDB; 7M3G; EM; 2.50 A; A/B=20-894.
DR PDB; 7M3J; EM; 4.10 A; A/B=20-894.
DR PDB; 7SIL; EM; 2.70 A; A/B=1-870.
DR PDB; 7SIM; EM; 2.70 A; A/B=1-870.
DR PDB; 7SIN; EM; 5.90 A; A/B=1-870.
DR PDBsum; 5FBH; -.
DR PDBsum; 5FBK; -.
DR PDBsum; 5K5S; -.
DR PDBsum; 5K5T; -.
DR PDBsum; 7DTT; -.
DR PDBsum; 7DTU; -.
DR PDBsum; 7DTV; -.
DR PDBsum; 7DTW; -.
DR PDBsum; 7E6T; -.
DR PDBsum; 7E6U; -.
DR PDBsum; 7M3E; -.
DR PDBsum; 7M3F; -.
DR PDBsum; 7M3G; -.
DR PDBsum; 7M3J; -.
DR PDBsum; 7SIL; -.
DR PDBsum; 7SIM; -.
DR PDBsum; 7SIN; -.
DR AlphaFoldDB; P41180; -.
DR SMR; P41180; -.
DR BioGRID; 107296; 22.
DR DIP; DIP-5975N; -.
DR ELM; P41180; -.
DR IntAct; P41180; 1.
DR STRING; 9606.ENSP00000420194; -.
DR BindingDB; P41180; -.
DR ChEMBL; CHEMBL1878; -.
DR DrugBank; DB11093; Calcium citrate.
DR DrugBank; DB11348; Calcium Phosphate.
DR DrugBank; DB14481; Calcium phosphate dihydrate.
DR DrugBank; DB01012; Cinacalcet.
DR DrugBank; DB12865; Etelcalcetide.
DR DrugBank; DB00994; Neomycin.
DR DrugBank; DB05695; NPS-2143.
DR DrugBank; DB05255; Ronacaleret.
DR DrugBank; DB00127; Spermine.
DR DrugCentral; P41180; -.
DR GuidetoPHARMACOLOGY; 54; -.
DR TCDB; 9.A.14.7.2; the g-protein-coupled receptor (gpcr) family.
DR GlyConnect; 1227; 2 N-Linked glycans (1 site).
DR GlyGen; P41180; 11 sites, 2 N-linked glycans (1 site).
DR iPTMnet; P41180; -.
DR PhosphoSitePlus; P41180; -.
DR BioMuta; CASR; -.
DR DMDM; 1168781; -.
DR MassIVE; P41180; -.
DR PaxDb; P41180; -.
DR PeptideAtlas; P41180; -.
DR PRIDE; P41180; -.
DR ProteomicsDB; 55410; -. [P41180-1]
DR ProteomicsDB; 55411; -. [P41180-2]
DR Antibodypedia; 16753; 701 antibodies from 43 providers.
DR DNASU; 846; -.
DR Ensembl; ENST00000498619.4; ENSP00000420194.1; ENSG00000036828.17. [P41180-2]
DR Ensembl; ENST00000638421.1; ENSP00000492190.1; ENSG00000036828.17. [P41180-1]
DR Ensembl; ENST00000639785.2; ENSP00000491584.2; ENSG00000036828.17. [P41180-1]
DR GeneID; 846; -.
DR KEGG; hsa:846; -.
DR MANE-Select; ENST00000639785.2; ENSP00000491584.2; NM_000388.4; NP_000379.3.
DR UCSC; uc003eev.5; human. [P41180-1]
DR CTD; 846; -.
DR DisGeNET; 846; -.
DR GeneCards; CASR; -.
DR GeneReviews; CASR; -.
DR HGNC; HGNC:1514; CASR.
DR HPA; ENSG00000036828; Tissue enriched (parathyroid).
DR MalaCards; CASR; -.
DR MIM; 145980; phenotype.
DR MIM; 239200; phenotype.
DR MIM; 601198; phenotype.
DR MIM; 601199; gene.
DR MIM; 612899; phenotype.
DR neXtProt; NX_P41180; -.
DR OpenTargets; ENSG00000036828; -.
DR Orphanet; 428; Autosomal dominant hypocalcemia.
DR Orphanet; 93372; Familial hypocalciuric hypercalcemia type 1.
DR Orphanet; 676; Hereditary chronic pancreatitis.
DR Orphanet; 417; Neonatal severe primary hyperparathyroidism.
DR PharmGKB; PA26097; -.
DR VEuPathDB; HostDB:ENSG00000036828; -.
DR eggNOG; KOG1056; Eukaryota.
DR GeneTree; ENSGT00940000157596; -.
DR HOGENOM; CLU_005389_0_0_1; -.
DR InParanoid; P41180; -.
DR OMA; CPDDSWS; -.
DR OrthoDB; 327938at2759; -.
DR PhylomeDB; P41180; -.
DR PathwayCommons; P41180; -.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR Reactome; R-HSA-420499; Class C/3 (Metabotropic glutamate/pheromone receptors).
DR SignaLink; P41180; -.
DR SIGNOR; P41180; -.
DR BioGRID-ORCS; 846; 27 hits in 1072 CRISPR screens.
DR ChiTaRS; CASR; human.
DR GeneWiki; Calcium-sensing_receptor; -.
DR GenomeRNAi; 846; -.
DR Pharos; P41180; Tclin.
DR PRO; PR:P41180; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P41180; protein.
DR Bgee; ENSG00000036828; Expressed in islet of Langerhans and 52 other tissues.
DR ExpressionAtlas; P41180; baseline and differential.
DR Genevisible; P41180; HS.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0016597; F:amino acid binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005178; F:integrin binding; IEA:Ensembl.
DR GO; GO:0004435; F:phosphatidylinositol phospholipase C activity; TAS:ProtInc.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0032782; P:bile acid secretion; IEA:Ensembl.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IEA:Ensembl.
DR GO; GO:0070509; P:calcium ion import; IDA:UniProtKB.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0071404; P:cellular response to low-density lipoprotein particle stimulus; IEA:Ensembl.
DR GO; GO:1901653; P:cellular response to peptide; IEA:Ensembl.
DR GO; GO:0071305; P:cellular response to vitamin D; IEA:Ensembl.
DR GO; GO:0007635; P:chemosensory behavior; TAS:ProtInc.
DR GO; GO:1902476; P:chloride transmembrane transport; IEA:Ensembl.
DR GO; GO:0005513; P:detection of calcium ion; IDA:UniProtKB.
DR GO; GO:0060613; P:fat pad development; IEA:Ensembl.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0001503; P:ossification; TAS:ProtInc.
DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0032781; P:positive regulation of ATP-dependent activity; IEA:Ensembl.
DR GO; GO:0090280; P:positive regulation of calcium ion import; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0050927; P:positive regulation of positive chemotaxis; IEA:Ensembl.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:Ensembl.
DR GO; GO:0051924; P:regulation of calcium ion transport; IBA:GO_Central.
DR GO; GO:0071774; P:response to fibroblast growth factor; IEA:Ensembl.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0042311; P:vasodilation; IEA:Ensembl.
DR Gene3D; 2.10.50.30; -; 1.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR000337; GPCR_3.
DR InterPro; IPR011500; GPCR_3_9-Cys_dom.
DR InterPro; IPR038550; GPCR_3_9-Cys_sf.
DR InterPro; IPR017978; GPCR_3_C.
DR InterPro; IPR000068; GPCR_3_Ca_sens_rcpt-rel.
DR InterPro; IPR017979; GPCR_3_CS.
DR InterPro; IPR028082; Peripla_BP_I.
DR PANTHER; PTHR24061; PTHR24061; 1.
DR Pfam; PF00003; 7tm_3; 1.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF07562; NCD3G; 1.
DR PRINTS; PR00592; CASENSINGR.
DR PRINTS; PR00248; GPCRMGR.
DR SUPFAM; SSF53822; SSF53822; 1.
DR PROSITE; PS00979; G_PROTEIN_RECEP_F3_1; 1.
DR PROSITE; PS00980; G_PROTEIN_RECEP_F3_2; 1.
DR PROSITE; PS00981; G_PROTEIN_RECEP_F3_3; 1.
DR PROSITE; PS50259; G_PROTEIN_RECEP_F3_4; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell membrane;
KW Disease variant; Disulfide bond; Epilepsy; G-protein coupled receptor;
KW Glycoprotein; Membrane; Metal-binding; Phosphoprotein; Receptor;
KW Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..1078
FT /note="Extracellular calcium-sensing receptor"
FT /id="PRO_0000012946"
FT TOPO_DOM 20..612
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 613..635
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 636..649
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 650..670
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 671..681
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 682..700
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 701..724
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 725..745
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 746..769
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 770..792
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 793..805
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 806..828
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 829..836
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 837..862
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 863..1078
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 22..188
FT /note="Ligand-binding 1 (LB1)"
FT /evidence="ECO:0000303|PubMed:17360426"
FT REGION 189..324
FT /note="Ligand-binding 2 (LB2)"
FT /evidence="ECO:0000303|PubMed:17360426"
FT REGION 542..612
FT /note="Cysteine-rich (CR)"
FT /evidence="ECO:0000303|PubMed:17360426"
FT REGION 880..900
FT /note="Interaction with RNF19A"
FT /evidence="ECO:0000269|PubMed:16513638"
FT REGION 892..963
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 986..1006
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1030..1055
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 894..963
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 66..70
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /ligand_note="required for structural stability of the
FT receptor"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT BINDING 81
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 84
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547, ECO:0007744|PDB:5FBK,
FT ECO:0007744|PDB:5K5S"
FT BINDING 87
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 88
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 100
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S, ECO:0007744|PDB:5K5T"
FT BINDING 145
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT BINDING 147
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 168
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 170
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 231
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT BINDING 234
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT BINDING 297
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT BINDING 415..417
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /ligand_note="required for structural stability of the
FT receptor"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT BINDING 557
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0007744|PDB:5K5S"
FT SITE 482
FT /note="Important for ability of agonist AMG 416 to activate
FT G-protein-coupled receptor activity"
FT /evidence="ECO:0000269|PubMed:26290606"
FT MOD_RES 920
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT MOD_RES 1061
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT CARBOHYD 90
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 130
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 261
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 287
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 386
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 400
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 446
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 468
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 488
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 541
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT CARBOHYD 594
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:27434672"
FT DISULFID 60..101
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT DISULFID 129
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547"
FT DISULFID 131
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000305|PubMed:27386547"
FT DISULFID 236..561
FT /evidence="ECO:0000269|PubMed:27434672"
FT DISULFID 358..395
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT DISULFID 437..449
FT /evidence="ECO:0000269|PubMed:27386547,
FT ECO:0000269|PubMed:27434672, ECO:0007744|PDB:5FBH,
FT ECO:0007744|PDB:5FBK, ECO:0007744|PDB:5K5S"
FT DISULFID 542..562
FT /evidence="ECO:0000269|PubMed:27434672"
FT DISULFID 546..565
FT /evidence="ECO:0000269|PubMed:27434672"
FT DISULFID 568..582
FT /evidence="ECO:0000269|PubMed:27434672"
FT DISULFID 585..598
FT /evidence="ECO:0000269|PubMed:27434672"
FT VAR_SEQ 536
FT /note="E -> EPLTFVLSVLQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:7759551"
FT /id="VSP_002035"
FT VARIANT 11
FT /note="L -> S (in HHC1; demonstrates reduced intracellular
FT and plasma membrane expression and signaling to the MAPK
FT pathway in response to extracellular calcium relative to
FT wild-type; fails to be inserted in the microsomes and does
FT not undergo proper glycosylation; dbSNP:rs200673016)"
FT /evidence="ECO:0000269|PubMed:15879434"
FT /id="VAR_058046"
FT VARIANT 13
FT /note="L -> P (in HHC1; has a dose-response curve shifted
FT to the right relative to that of wild-type; demonstrates
FT reduced intracellular and plasma membrane expression and
FT signaling to the MAPK pathway in response to extracellular
FT calcium relative to wild-type; fails to be inserted in the
FT microsomes and does not undergo proper glycosylation;
FT dbSNP:rs104893717)"
FT /evidence="ECO:0000269|PubMed:15579740,
FT ECO:0000269|PubMed:15879434"
FT /id="VAR_058047"
FT VARIANT 14
FT /note="T -> A (does not demonstrate reduced intracellular
FT and plasma membrane expression and signaling to the MAPK
FT pathway in response to extracellular calcium relative to
FT wild-type; does not fail to be inserted in the microsomes
FT and does undergo proper glycosylation; dbSNP:rs199515839)"
FT /evidence="ECO:0000269|PubMed:15879434"
FT /id="VAR_058048"
FT VARIANT 21
FT /note="G -> R (in HHC1; dbSNP:rs1064794290)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058049"
FT VARIANT 27
FT /note="Q -> R (found in a patient with primary
FT hyperparathyroidism detected at adulthood; mutant CASR is
FT activated by a higher calcium concentrations than the wild-
FT type)"
FT /evidence="ECO:0000269|PubMed:10468915"
FT /id="VAR_065198"
FT VARIANT 39
FT /note="P -> A (in HHC1; dbSNP:rs121909262)"
FT /evidence="ECO:0000269|PubMed:7673400"
FT /id="VAR_003585"
FT VARIANT 42
FT /note="F -> S (in HHC1; dbSNP:rs1553765909)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078139"
FT VARIANT 47
FT /note="K -> N (in HYPOC1; the EC(50) of the mutant is
FT significantly lower than that of wild-type;
FT dbSNP:rs104893702)"
FT /evidence="ECO:0000269|PubMed:9920108"
FT /id="VAR_058050"
FT VARIANT 53
FT /note="S -> P (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:8636323"
FT /id="VAR_078140"
FT VARIANT 55
FT /note="P -> L (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs886041154)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8878438"
FT /id="VAR_078141"
FT VARIANT 62
FT /note="R -> M (in HHC1; mild; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909265)"
FT /evidence="ECO:0000269|PubMed:7726161,
FT ECO:0000269|PubMed:8702647"
FT /id="VAR_003586"
FT VARIANT 66
FT /note="R -> C (in HHC1; does not affect homodimerization;
FT impaired N-glycosylation; impaired cell membrane
FT localization; decreased G-protein coupled receptor
FT signaling pathway; dbSNP:rs121909266)"
FT /evidence="ECO:0000269|PubMed:16740594,
FT ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:8702647"
FT /id="VAR_003587"
FT VARIANT 66
FT /note="R -> H (in HHC1; does not affect homodimerization;
FT impaired N-glycosylation; impaired cell membrane
FT localization; decreased G-protein coupled receptor
FT signaling pathway; dbSNP:rs1276839362)"
FT /evidence="ECO:0000269|PubMed:16740594,
FT ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:27434672"
FT /id="VAR_078142"
FT VARIANT 81
FT /note="I -> M (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_078143"
FT VARIANT 100
FT /note="T -> I (in NSHPT; Abolished G-protein coupled
FT receptor activity)"
FT /evidence="ECO:0000269|PubMed:14985373,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_065199"
FT VARIANT 110
FT /note="A -> T (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:23966241"
FT /id="VAR_078144"
FT VARIANT 116
FT /note="A -> T (in HYPOC1; dbSNP:rs104893691)"
FT /evidence="ECO:0000269|PubMed:8733126"
FT /id="VAR_003588"
FT VARIANT 118
FT /note="N -> K (in HYPOC1; the mutation shifts the
FT concentration-response curve to the left and increases
FT maximal activity; dbSNP:rs104893695)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:9253358"
FT /id="VAR_058051"
FT VARIANT 122
FT /note="S -> C (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:23966241"
FT /id="VAR_078145"
FT VARIANT 125
FT /note="L -> F (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078146"
FT VARIANT 125
FT /note="L -> P (in HYPOC1; shifts the concentration-response
FT curve of calcium ions to the left; dbSNP:rs104893708)"
FT /evidence="ECO:0000269|PubMed:12107202"
FT /id="VAR_058052"
FT VARIANT 127
FT /note="E -> A (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909260)"
FT /evidence="ECO:0000269|PubMed:7874174,
FT ECO:0000269|PubMed:8702647"
FT /id="VAR_003589"
FT VARIANT 128
FT /note="F -> L (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; dbSNP:rs104893696)"
FT /evidence="ECO:0000269|PubMed:8813042,
FT ECO:0000269|PubMed:8878438"
FT /id="VAR_058053"
FT VARIANT 129
FT /note="C -> R (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078147"
FT VARIANT 131
FT /note="C -> W (in HYPOC1; associated with clinical features
FT of Bartter syndrome; dbSNP:rs121909267)"
FT /evidence="ECO:0000269|PubMed:12241879"
FT /id="VAR_058054"
FT VARIANT 136
FT /note="P -> L (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization)"
FT /evidence="ECO:0000269|PubMed:25766501"
FT /id="VAR_078148"
FT VARIANT 138
FT /note="T -> M (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909263)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:8702647"
FT /id="VAR_003590"
FT VARIANT 143
FT /note="G -> E (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909264)"
FT /evidence="ECO:0000269|PubMed:7726161,
FT ECO:0000269|PubMed:8702647"
FT /id="VAR_003591"
FT VARIANT 143
FT /note="G -> R (in HHC1; dbSNP:rs769256610)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078149"
FT VARIANT 151
FT /note="T -> M (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; dbSNP:rs104893694)"
FT /evidence="ECO:0000269|PubMed:8698326,
FT ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:8878438"
FT /id="VAR_058055"
FT VARIANT 158
FT /note="G -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078150"
FT VARIANT 159
FT /note="L -> P (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:22114145,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_078151"
FT VARIANT 166
FT /note="S -> G (in HHC1; dbSNP:rs193922441)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078152"
FT VARIANT 171
FT /note="S -> N (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058056"
FT VARIANT 172
FT /note="R -> G (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs201851934)"
FT /evidence="ECO:0000269|PubMed:23966241,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_078153"
FT VARIANT 174
FT /note="L -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:9298824"
FT /id="VAR_003592"
FT VARIANT 178
FT /note="N -> D (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs1060502855)"
FT /evidence="ECO:0000269|PubMed:8878438"
FT /id="VAR_078154"
FT VARIANT 180
FT /note="F -> C (in HHC1; although the mutant receptor is
FT expressed normally at the cell surface it is unresponsive
FT with respect to intracellular signaling (MAPK activation)
FT to increases in extracellular calcium concentrations;
FT dbSNP:rs121909268)"
FT /evidence="ECO:0000269|PubMed:17473068"
FT /id="VAR_058057"
FT VARIANT 185
FT /note="R -> Q (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs104893689)"
FT /evidence="ECO:0000269|PubMed:7916660,
FT ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8702647"
FT /id="VAR_003593"
FT VARIANT 191
FT /note="E -> K (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; dbSNP:rs104893697)"
FT /evidence="ECO:0000269|PubMed:8813042,
FT ECO:0000269|PubMed:8878438"
FT /id="VAR_058058"
FT VARIANT 215
FT /note="D -> G (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000269|PubMed:8636323"
FT /id="VAR_078155"
FT VARIANT 220
FT /note="R -> W (in HHC1; dbSNP:rs1482119762)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078156"
FT VARIANT 221
FT /note="P -> L (in HYPOC1; dbSNP:rs397514728)"
FT /evidence="ECO:0000269|PubMed:22789683"
FT /id="VAR_078157"
FT VARIANT 221
FT /note="P -> Q (in HHC1; dbSNP:rs397514728)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058059"
FT VARIANT 221
FT /note="P -> S (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:8878438"
FT /id="VAR_078158"
FT VARIANT 225
FT /note="K -> T (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058060"
FT VARIANT 227
FT /note="R -> L (in NSHPT; decreased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization; dbSNP:rs28936684)"
FT /evidence="ECO:0000269|PubMed:15572418,
FT ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:8675635,
FT ECO:0000269|PubMed:8878438"
FT /id="VAR_003594"
FT VARIANT 227
FT /note="R -> Q (in HHC1; G-protein coupled receptor
FT signaling pathway; less markedly impaired relative to wild-
FT type than L-227; does not affect cell membrane
FT localization; dbSNP:rs28936684)"
FT /evidence="ECO:0000269|PubMed:15572418,
FT ECO:0000269|PubMed:7726161"
FT /id="VAR_003595"
FT VARIANT 228
FT /note="E -> K (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078159"
FT VARIANT 250
FT /note="E -> K (in dbSNP:rs62269092)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058061"
FT VARIANT 271
FT /note="S -> F (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058062"
FT VARIANT 297
FT /note="E -> K (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909259)"
FT /evidence="ECO:0000269|PubMed:27434672,
FT ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:8702647"
FT /id="VAR_003596"
FT VARIANT 336
FT /note="Missing (in NSHPT)"
FT /evidence="ECO:0000269|PubMed:14985373"
FT /id="VAR_065200"
FT VARIANT 339
FT /note="P -> T (mutation found in a patient with primary
FT hyperparathyroidism detected at adulthood; inactivating
FT mutation; mutant CASR is activated by a higher calcium
FT concentrations than the wild-type)"
FT /evidence="ECO:0000269|PubMed:20846291"
FT /id="VAR_065201"
FT VARIANT 354
FT /note="E -> A (in EIG8; patients present juvenile myoclonus
FT epilepsy)"
FT /evidence="ECO:0000269|PubMed:18756473"
FT /id="VAR_060206"
FT VARIANT 397
FT /note="G -> R (in HHC1; dbSNP:rs1064794291)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058063"
FT VARIANT 459
FT /note="Q -> R (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization)"
FT /evidence="ECO:0000269|PubMed:19789209"
FT /id="VAR_078160"
FT VARIANT 465
FT /note="R -> Q (in HHC1; loss-of-function mutation; the
FT quantity of the mutant receptor is higher than that of the
FT wild-type receptor; dose-response curves show that the
FT mutation significantly reduces the sensitivity of the
FT receptor to extracellular calcium concentrations;
FT dbSNP:rs104893716)"
FT /evidence="ECO:0000269|PubMed:16598859"
FT /id="VAR_058064"
FT VARIANT 509
FT /note="G -> R (in HHC1; dbSNP:rs193922423)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058065"
FT VARIANT 549
FT /note="G -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078161"
FT VARIANT 550
FT /note="T -> I (in HHC1; decreased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:21566075"
FT /id="VAR_078162"
FT VARIANT 551
FT /note="R -> K (in NSHPT; decreased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization; dbSNP:rs1060502861)"
FT /evidence="ECO:0000269|PubMed:17555508,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_078163"
FT VARIANT 553
FT /note="G -> R (in HHC1; dbSNP:rs104893719)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058066"
FT VARIANT 555
FT /note="I -> V (in HHC1; dbSNP:rs777646067)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058067"
FT VARIANT 557
FT /note="G -> E (in HHC1; Abolished G-protein coupled
FT receptor activity)"
FT /evidence="ECO:0000269|PubMed:11762699,
FT ECO:0000269|PubMed:27434672"
FT /id="VAR_012649"
FT VARIANT 562
FT /note="C -> Y (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911,
FT ECO:0000269|PubMed:19179454"
FT /id="VAR_058068"
FT VARIANT 565
FT /note="C -> G (in HHC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078164"
FT VARIANT 569
FT /note="P -> H (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:23966241"
FT /id="VAR_078165"
FT VARIANT 571
FT /note="G -> W (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization)"
FT /evidence="ECO:0000269|PubMed:26386835"
FT /id="VAR_078166"
FT VARIANT 582
FT /note="C -> F (in HHC1; dbSNP:rs104893690)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058069"
FT VARIANT 582
FT /note="C -> Y (in NSHPT and HHC1; dbSNP:rs104893690)"
FT /evidence="ECO:0000269|PubMed:17698911,
FT ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:8675635"
FT /id="VAR_003597"
FT VARIANT 583..1078
FT /note="Missing (in HHC1; impaired homodimerization;
FT impaired cell membrane localization)"
FT /evidence="ECO:0000269|PubMed:16740594,
FT ECO:0000269|PubMed:19179454"
FT /id="VAR_078167"
FT VARIANT 604
FT /note="E -> K (in HYPOC1; there is a significant leftward
FT shift in the concentration response curves for the effects
FT of extracellular calcium on both intracellular calcium
FT mobilization and MAPK activity; dbSNP:rs104893712)"
FT /evidence="ECO:0000269|PubMed:12574188,
FT ECO:0000269|PubMed:19179454"
FT /id="VAR_058070"
FT VARIANT 612
FT /note="F -> S (in HYPOC1; dbSNP:rs104893698)"
FT /evidence="ECO:0000269|PubMed:8813042"
FT /id="VAR_058071"
FT VARIANT 616
FT /note="L -> V (in HYPOC1; does not affect the total
FT accumulation of inositol phosphates as a function of
FT extracellular calcium concentrations in transfected cells;
FT dbSNP:rs104893703)"
FT /evidence="ECO:0000269|PubMed:10487661"
FT /id="VAR_015414"
FT VARIANT 623
FT /note="G -> D (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058072"
FT VARIANT 650
FT /note="L -> P (in NSHPT)"
FT /evidence="ECO:0000269|PubMed:14985373"
FT /id="VAR_065202"
FT VARIANT 657
FT /note="S -> Y (in HHC1)"
FT /evidence="ECO:0000269|PubMed:8636323"
FT /id="VAR_078168"
FT VARIANT 661
FT /note="C -> Y (in HHC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078169"
FT VARIANT 670
FT /note="G -> E (in NSHPT; dbSNP:rs104893700)"
FT /evidence="ECO:0000269|PubMed:9253359"
FT /id="VAR_058073"
FT VARIANT 670
FT /note="G -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058074"
FT VARIANT 680
FT /note="R -> H (in HHC1; dbSNP:rs773146939)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078170"
FT VARIANT 681
FT /note="Q -> H (in HYPOC1; dbSNP:rs121909261)"
FT /evidence="ECO:0000269|PubMed:8733126"
FT /id="VAR_003598"
FT VARIANT 681
FT /note="Q -> R (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization)"
FT /evidence="ECO:0000269|PubMed:22789683"
FT /id="VAR_078171"
FT VARIANT 686
FT /note="I -> V (in EIG8; patients present juvenile myoclonus
FT epilepsy; dbSNP:rs753013993)"
FT /evidence="ECO:0000269|PubMed:18756473"
FT /id="VAR_060207"
FT VARIANT 689
FT /note="V -> M (in NSHPT)"
FT /evidence="ECO:0000269|PubMed:14985373"
FT /id="VAR_065203"
FT VARIANT 697
FT /note="V -> M (in HHC1)"
FT /evidence="ECO:0000269|PubMed:21643651"
FT /id="VAR_065494"
FT VARIANT 707
FT /note="E -> V (in HHC1; decreased protein level)"
FT /evidence="ECO:0000269|PubMed:25104082"
FT /id="VAR_078172"
FT VARIANT 727
FT /note="L -> Q (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization; dbSNP:rs104893718)"
FT /evidence="ECO:0000269|PubMed:16608894,
FT ECO:0000269|PubMed:22789683"
FT /id="VAR_058075"
FT VARIANT 728
FT /note="V -> F (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058076"
FT VARIANT 742
FT /note="W -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058077"
FT VARIANT 748
FT /note="P -> R (in HHC1)"
FT /evidence="ECO:0000269|PubMed:8636323"
FT /id="VAR_078173"
FT VARIANT 761
FT /note="Missing (in HHC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078174"
FT VARIANT 767
FT /note="E -> K (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:15551332"
FT /id="VAR_021019"
FT VARIANT 773
FT /note="L -> R (in HYPOC1; the mutation shifts the
FT concentration-response curve to the left and increases
FT maximal activity; dbSNP:rs104893699)"
FT /evidence="ECO:0000269|PubMed:9253358"
FT /id="VAR_058078"
FT VARIANT 774
FT /note="G -> S (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; does not affect cell membrane
FT localization)"
FT /evidence="ECO:0000269|PubMed:25104082"
FT /id="VAR_078175"
FT VARIANT 788
FT /note="F -> C (in HYPOC1; leftward shift in the
FT concentration-response curve for the mutant receptor; cells
FT cotransfected with both the wild-type and the mutant
FT receptor show an EC(50) similar to the mutant; a gain-of-
FT function mutation rendering the receptor more sensitive
FT than normal to activation; dbSNP:rs104893701)"
FT /evidence="ECO:0000269|PubMed:9661634"
FT /id="VAR_058079"
FT VARIANT 788
FT /note="F -> L (in HYPOC1; induces a significant shift to
FT the left relative to the wild-type protein in the MAPK
FT response to increasing extracellular calcium
FT concentrations; dbSNP:rs886041537 and dbSNP:rs104893711)"
FT /evidence="ECO:0000269|PubMed:12915654"
FT /id="VAR_058080"
FT VARIANT 795
FT /note="R -> W (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs121909258)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:7916660,
FT ECO:0000269|PubMed:8702647"
FT /id="VAR_003599"
FT VARIANT 802
FT /note="N -> I (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:19179454,
FT ECO:0000269|PubMed:23169696"
FT /id="VAR_078176"
FT VARIANT 802
FT /note="N -> S (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs140022350)"
FT /evidence="ECO:0000269|PubMed:23169696"
FT /id="VAR_078177"
FT VARIANT 806
FT /note="F -> S (in HYPOC1; does not produce a significant
FT activating effect; decreased cell surface receptor
FT expression; dbSNP:rs104893693)"
FT /evidence="ECO:0000269|PubMed:8733126,
FT ECO:0000269|PubMed:9253358"
FT /id="VAR_003600"
FT VARIANT 817
FT /note="V -> I (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs1057518933)"
FT /evidence="ECO:0000269|PubMed:8878438"
FT /id="VAR_078178"
FT VARIANT 820
FT /note="S -> F (in HYPOC1; the concentration-response curve
FT of the mutant receptor is left-shifted and its EC(50) is
FT significantly lower than that of the wild-type;
FT dbSNP:rs104893710)"
FT /evidence="ECO:0000269|PubMed:12050233"
FT /id="VAR_058081"
FT VARIANT 830
FT /note="G -> S (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078179"
FT VARIANT 832
FT /note="F -> L (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078180"
FT VARIANT 832
FT /note="F -> S (in HYPOC1)"
FT /evidence="ECO:0000269|PubMed:19179454"
FT /id="VAR_078181"
FT VARIANT 839
FT /note="I -> T (in HYPOC1; increased G-protein coupled
FT receptor signaling pathway)"
FT /evidence="ECO:0000269|PubMed:23966241"
FT /id="VAR_078182"
FT VARIANT 843
FT /note="A -> E (in HYPOC1; also in HYPOC1 associated with
FT clinical features of Bartter syndrome; shifts the
FT concentration-response curve of calcium ions to the left;
FT dbSNP:rs104893706)"
FT /evidence="ECO:0000269|PubMed:12107202,
FT ECO:0000269|PubMed:12241879"
FT /id="VAR_058082"
FT VARIANT 851
FT /note="C -> S (in dbSNP:rs200777304)"
FT /evidence="ECO:0000269|PubMed:8733126"
FT /id="VAR_003601"
FT VARIANT 881
FT /note="F -> L (probable disease-associated variant found in
FT a patient with hypercalciuric hypercalcemia; mutant CASR
FT has a right-shifted dose-response to extracellular calcium
FT concentrations; activated by a higher calcium
FT concentrations than the wild-type; dbSNP:rs104893704)"
FT /evidence="ECO:0000269|PubMed:10843194"
FT /id="VAR_058083"
FT VARIANT 886
FT /note="R -> W (in HHC1)"
FT /evidence="ECO:0000269|PubMed:17698911"
FT /id="VAR_058084"
FT VARIANT 898
FT /note="R -> Q (in EIG8; dbSNP:rs121909269)"
FT /evidence="ECO:0000269|PubMed:18756473"
FT /id="VAR_060208"
FT VARIANT 951
FT /note="P -> T (in dbSNP:rs4987051)"
FT /id="VAR_020220"
FT VARIANT 972
FT /note="T -> M (in HHC1; decreased G-protein coupled
FT receptor signaling pathway; dbSNP:rs200620134)"
FT /evidence="ECO:0000269|PubMed:25292184"
FT /id="VAR_078183"
FT VARIANT 986
FT /note="A -> S (associated with high serum level of calcium;
FT is also a potential predisposing factor in disorders of
FT bone and mineral metabolism; dbSNP:rs1801725)"
FT /evidence="ECO:0000269|PubMed:10023897,
FT ECO:0000269|PubMed:11161843, ECO:0000269|PubMed:14985373,
FT ECO:0000269|PubMed:15531522, ECO:0000269|PubMed:16598859,
FT ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:17698911,
FT ECO:0000269|PubMed:18756473, ECO:0000269|PubMed:19789209,
FT ECO:0000269|PubMed:8636323, ECO:0000269|Ref.5"
FT /id="VAR_014450"
FT VARIANT 988
FT /note="A -> G (in EIG8; patients present juvenile myoclonus
FT epilepsy)"
FT /evidence="ECO:0000269|PubMed:18756473"
FT /id="VAR_060209"
FT VARIANT 988
FT /note="A -> V (in EIG8; patients present juvenile myoclonus
FT epilepsy; dbSNP:rs759027000)"
FT /evidence="ECO:0000269|PubMed:18756473"
FT /id="VAR_060210"
FT VARIANT 990
FT /note="R -> G (associated with low serum level of calcium;
FT dbSNP:rs1042636)"
FT /evidence="ECO:0000269|PubMed:12050233,
FT ECO:0000269|PubMed:14985373, ECO:0000269|PubMed:15531522,
FT ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:17698911,
FT ECO:0000269|PubMed:18756473, ECO:0000269|PubMed:7759551,
FT ECO:0000269|PubMed:8636323, ECO:0000269|Ref.5"
FT /id="VAR_020221"
FT VARIANT 1011
FT /note="E -> Q (in dbSNP:rs1801726)"
FT /evidence="ECO:0000269|PubMed:14985373,
FT ECO:0000269|PubMed:15531522, ECO:0000269|PubMed:17698911,
FT ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:8636323,
FT ECO:0000269|Ref.5"
FT /id="VAR_014451"
FT MUTAGEN 69
FT /note="R->E: Abolishes G-protein coupled receptor signaling
FT pathway."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 102
FT /note="N->I: Abolishes G-protein coupled receptor
FT activity."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 145
FT /note="T->A: Abolishes G-protein coupled receptor
FT activity."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 147
FT /note="S->A: Nearly abolished G-protein coupled receptor
FT activity."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 170
FT /note="S->A: Abolishes G-protein coupled receptor
FT activity."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 218
FT /note="Y->S: Abolishes G-protein coupled receptor
FT activity."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 297
FT /note="E->I: Abolishes ability to sense calcium or
FT magnesium levels."
FT /evidence="ECO:0000269|PubMed:27386547"
FT MUTAGEN 417
FT /note="S->L: Abolishes G-protein coupled receptor signaling
FT pathway."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 458
FT /note="W->A: Decreased G-protein coupled receptor signaling
FT pathway."
FT /evidence="ECO:0000269|PubMed:27434672"
FT MUTAGEN 482
FT /note="C->S,Y: Abolishes ability of agonist AMG 416 to
FT activate G-protein-coupled receptor activity."
FT /evidence="ECO:0000269|PubMed:26290606"
FT CONFLICT 857
FT /note="I -> T (in Ref. 3; BAA09453)"
FT /evidence="ECO:0000305"
FT CONFLICT 878
FT /note="A -> R (in Ref. 3; BAA09453)"
FT /evidence="ECO:0000305"
FT CONFLICT 926
FT /note="Q -> R (in Ref. 2; AAA86503)"
FT /evidence="ECO:0000305"
FT STRAND 22..24
FT /evidence="ECO:0007829|PDB:7M3F"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 31..38
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 40..44
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 51..53
FT /evidence="ECO:0007829|PDB:7SIL"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 65..82
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 85..90
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 93..99
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 104..114
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 116..123
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 125..128
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:7E6T"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:7E6T"
FT STRAND 138..142
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 147..159
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 164..168
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 172..175
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 177..179
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 183..187
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 191..203
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 208..216
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 219..232
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 237..243
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 249..261
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 266..270
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 273..285
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 292..295
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 297..300
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 303..305
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 308..310
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 311..314
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 318..322
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 330..335
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 339..341
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 343..345
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 348..356
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 358..360
FT /evidence="ECO:0007829|PDB:5K5T"
FT HELIX 374..378
FT /evidence="ECO:0007829|PDB:5K5T"
FT STRAND 384..386
FT /evidence="ECO:0007829|PDB:5K5T"
FT HELIX 387..389
FT /evidence="ECO:0007829|PDB:5K5T"
FT HELIX 401..403
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 407..409
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 416..435
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 441..444
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 445..447
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 452..454
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 457..465
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 468..470
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 472..474
FT /evidence="ECO:0007829|PDB:7DTV"
FT STRAND 476..478
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 481..485
FT /evidence="ECO:0007829|PDB:5K5T"
FT STRAND 489..496
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 498..500
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 502..511
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 513..515
FT /evidence="ECO:0007829|PDB:5FBH"
FT STRAND 519..523
FT /evidence="ECO:0007829|PDB:5FBK"
FT HELIX 525..527
FT /evidence="ECO:0007829|PDB:5FBK"
FT TURN 531..533
FT /evidence="ECO:0007829|PDB:5FBK"
FT STRAND 550..554
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 556..558
FT /evidence="ECO:0007829|PDB:5K5T"
FT STRAND 563..567
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 576..578
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 579..581
FT /evidence="ECO:0007829|PDB:7E6T"
FT STRAND 587..591
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 596..600
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 602..604
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 608..610
FT /evidence="ECO:0007829|PDB:7SIL"
FT HELIX 611..636
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 637..639
FT /evidence="ECO:0007829|PDB:7SIL"
FT HELIX 641..645
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 650..663
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 664..668
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 669..671
FT /evidence="ECO:0007829|PDB:7SIL"
FT TURN 674..678
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 681..696
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 701..705
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 725..745
FT /evidence="ECO:0007829|PDB:7M3G"
FT STRAND 749..753
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 755..757
FT /evidence="ECO:0007829|PDB:7E6T"
FT STRAND 758..766
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 771..793
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 794..796
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 800..802
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 803..820
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 822..827
FT /evidence="ECO:0007829|PDB:7M3G"
FT TURN 829..831
FT /evidence="ECO:0007829|PDB:7M3F"
FT HELIX 834..852
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 854..862
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 863..865
FT /evidence="ECO:0007829|PDB:7M3E"
FT TURN 866..868
FT /evidence="ECO:0007829|PDB:7M3E"
FT HELIX 869..872
FT /evidence="ECO:0007829|PDB:7M3G"
FT HELIX 880..885
FT /evidence="ECO:0007829|PDB:7M3G"
SQ SEQUENCE 1078 AA; 120675 MW; D60C57C6C743FC06 CRC64;
MAFYSCCWVL LALTWHTSAY GPDQRAQKKG DIILGGLFPI HFGVAAKDQD LKSRPESVEC
IRYNFRGFRW LQAMIFAIEE INSSPALLPN LTLGYRIFDT CNTVSKALEA TLSFVAQNKI
DSLNLDEFCN CSEHIPSTIA VVGATGSGVS TAVANLLGLF YIPQVSYASS SRLLSNKNQF
KSFLRTIPND EHQATAMADI IEYFRWNWVG TIAADDDYGR PGIEKFREEA EERDICIDFS
ELISQYSDEE EIQHVVEVIQ NSTAKVIVVF SSGPDLEPLI KEIVRRNITG KIWLASEAWA
SSSLIAMPQY FHVVGGTIGF ALKAGQIPGF REFLKKVHPR KSVHNGFAKE FWEETFNCHL
QEGAKGPLPV DTFLRGHEES GDRFSNSSTA FRPLCTGDEN ISSVETPYID YTHLRISYNV
YLAVYSIAHA LQDIYTCLPG RGLFTNGSCA DIKKVEAWQV LKHLRHLNFT NNMGEQVTFD
ECGDLVGNYS IINWHLSPED GSIVFKEVGY YNVYAKKGER LFINEEKILW SGFSREVPFS
NCSRDCLAGT RKGIIEGEPT CCFECVECPD GEYSDETDAS ACNKCPDDFW SNENHTSCIA
KEIEFLSWTE PFGIALTLFA VLGIFLTAFV LGVFIKFRNT PIVKATNREL SYLLLFSLLC
CFSSSLFFIG EPQDWTCRLR QPAFGISFVL CISCILVKTN RVLLVFEAKI PTSFHRKWWG
LNLQFLLVFL CTFMQIVICV IWLYTAPPSS YRNQELEDEI IFITCHEGSL MALGFLIGYT
CLLAAICFFF AFKSRKLPEN FNEAKFITFS MLIFFIVWIS FIPAYASTYG KFVSAVEVIA
ILAASFGLLA CIFFNKIYII LFKPSRNTIE EVRCSTAAHA FKVAARATLR RSNVSRKRSS
SLGGSTGSTP SSSISSKSNS EDPFPQPERQ KQQQPLALTQ QEQQQQPLTL PQQQRSQQQP
RCKQKVIFGS GTVTFSLSFD EPQKNAMAHR NSTHQNSLEA QKSSDTLTRH EPLLPLQCGE
TDLDLTVQET GLQGPVGGDQ RPEVEDPEEL SPALVVSSSQ SFVISGGGST VTENVVNS
