P30968 (GNRHR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Gonadotropin-releasing hormone receptor
Short name=GnRH receptor
Short name=GnRH-R

Gene names

Name:	GNRHR
Synonyms:	GRHR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	328 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.
Subcellular location	Cell membrane; Multi-pass membrane protein.
Tissue specificity	Pituitary, ovary, testis, breast and prostate but not in liver and spleen.
Involvement in disease	Defects in GNRHR are a cause of idiopathic hypogonadotropic hypogonadism (IHH) [MIM:146110]. IHH is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Defects in GNRHR are a cause of fertile eunuch syndrome (FEUNS) [MIM:228300]. Fertile eunuch syndrome is a mild phenotypic form of HH going with the presence of normal testicular size and some degree of spermatogenesis. Ref.14
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing
Disease	Disease mutation Hypogonadotropic hypogonadism
Domain	Transmembrane Transmembrane helix
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	multicellular organismal development Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Traceable author statement Ref.2. Source: UniProtKB
Molecular function	gonadotropin-releasing hormone receptor activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P30968-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P30968-2)

Also known as: Truncated;

The sequence of this isoform differs from the canonical sequence as follows:
     176-328: YIFRMIHLAD...DPLIYGYFSL → PLHHPSFHHA...LLCPRNLVLV

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 328	328	Gonadotropin-releasing hormone receptor		PRO_0000069487
Regions
	Topological domain	1 – 38	38	Extracellular Potential
	Transmembrane	39 – 58	20	Helical; Name=1; Potential
	Topological domain	59 – 77	19	Cytoplasmic Potential
	Transmembrane	78 – 97	20	Helical; Name=2; Potential
	Topological domain	98 – 115	18	Extracellular Potential
	Transmembrane	116 – 137	22	Helical; Name=3; Potential
	Topological domain	138 – 164	27	Cytoplasmic Potential
	Transmembrane	165 – 184	20	Helical; Name=4; Potential
	Topological domain	185 – 212	28	Extracellular Potential
	Transmembrane	213 – 232	20	Helical; Name=5; Potential
	Topological domain	233 – 281	49	Cytoplasmic Potential
	Transmembrane	282 – 300	19	Helical; Name=6; Potential
	Topological domain	301 – 306	6	Extracellular Potential
	Transmembrane	307 – 326	20	Helical; Name=7; Potential
	Topological domain	327 – 328	2	Cytoplasmic Potential
Amino acid modifications
	Glycosylation	18	1	N-linked (GlcNAc...) Potential
	Glycosylation	102	1	N-linked (GlcNAc...) Potential
	Disulfide bond	114 ↔ 196		By similarity
Natural variations
	Alternative sequence	176 – 328	153	YIFRM…GYFSL → PLHHPSFHHADLQCKNHLHP DTGPSSGPPRTTTESVQEQY TKSTAEDSKNDGCICHFIYC LLDSLLCPRNLVLV in isoform 2.		VSP_001914
	Natural variant	10	1	N → K in IHH; is able to bind GnRH but with a reduced affinity in vitro. Ref.16		VAR_019311
	Natural variant	90	1	E → K in IHH; virtual abolition of GnRH agonist binding and agonist-stimulated phosphoinositide turnover; impairs GnRHR-effector coupling. Ref.15 Ref.17		VAR_019312
	Natural variant	106	1	Q → R in IHH and FEUNS; decreases but does not eliminate GnRH binding. Ref.9 Ref.11 Ref.14 Ref.16		VAR_019313
	Natural variant	129	1	A → D in IHH; complete loss of function. Ref.12		VAR_019314
	Natural variant	139	1	R → H in IHH; completely eliminates detectable GnRH-binding activity and prevents GnRH-induced stimulation of inositol phosphate accumulation in vitro. Ref.16		VAR_019315
	Natural variant	168	1	S → R in IHH; complete loss of the receptor-mediated signaling response. Ref.13		VAR_019316
	Natural variant	171	1	A → T in IHH; complete loss of ligand binding and receptor activation; specific receptor binding of radioisotope-labeled GnRH ligand is undetectable in transfected cells. Ref.18		VAR_019317
	Natural variant	217	1	S → R in IHH; altered hormone binding. Ref.11		VAR_019318
	Natural variant	262	1	R → Q in IHH; minimal effects upon receptor affinity but expression decreased; altered activation of phospholipase C. Ref.9 Ref.10 Ref.11 Ref.12		VAR_019319
	Natural variant	284	1	Y → C in IHH; minimal effects upon receptor affinity but receptor expression decreased. Ref.10 Corresponds to variant rs28933074 [ dbSNP | Ensembl ].		VAR_019320
Experimental info
	Sequence conflict	247	1	H → T in CAB17082. Ref.8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 1, 1993. Version 1. Checksum: D02B2EA2F4246D7B	FASTA	328	37,731
	10 20 30 40 50 60 MANSASPEQN QNHCSAINNS IPLMQGNLPT LTLSGKIRVT VTFFLFLLSA TFNASFLLKL 70 80 90 100 110 120 QKWTQKKEKG KKLSRMKLLL KHLTLANLLE TLIVMPLDGM WNITVQWYAG ELLCKVLSYL 130 140 150 160 170 180 KLFSMYAPAF MMVVISLDRS LAITRPLALK SNSKVGQSMV GLAWILSSVF AGPQLYIFRM 190 200 210 220 230 240 IHLADSSGQT KVFSQCVTHC SFSQWWHQAF YNFFTFSCLF IIPLFIMLIC NAKIIFTLTR 250 260 270 280 290 300 VLHQDPHELQ LNQSKNNIPR ARLKTLKMTV AFATSFTVCW TPYYVLGIWY WFDPEMLNRL 310 320 SDPVNHFFFL FAFLNPCFDP LIYGYFSL
	Isoform 2 (Truncated) [UniParc]. Checksum: 5801B1C5E5FBA64A	FASTA	249	27,727
	10 20 30 40 50 60 MANSASPEQN QNHCSAINNS IPLMQGNLPT LTLSGKIRVT VTFFLFLLSA TFNASFLLKL 70 80 90 100 110 120 QKWTQKKEKG KKLSRMKLLL KHLTLANLLE TLIVMPLDGM WNITVQWYAG ELLCKVLSYL 130 140 150 160 170 180 KLFSMYAPAF MMVVISLDRS LAITRPLALK SNSKVGQSMV GLAWILSSVF AGPQLPLHHP 190 200 210 220 230 240 SFHHADLQCK NHLHPDTGPS SGPPRTTTES VQEQYTKSTA EDSKNDGCIC HFIYCLLDSL LCPRNLVLV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor." Kakar S.S., Musgrove L.C., Devor D.C., Sellers J.C., Neill J.D. Biochem. Biophys. Res. Commun. 189:289-295(1992) [PubMed: 1333190] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Pituitary.
[2]	"Cloning and characterization of the human GnRH receptor." Chi L., Zhou W., Prikhozhan A., Flanagan C.A., Davidson J.S., Golembo M., Illing N., Millar R.P., Sealfon S.C. Mol. Cell. Endocrinol. 91:R1-R6(1993) [PubMed: 8386108] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Pituitary.
[3]	"The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary." Kakar S.S., Grizzle W.E., Neill J.D. Mol. Cell. Endocrinol. 106:145-149(1994) [PubMed: 7534732] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Molecular structure of the human gonadotropin-releasing hormone receptor gene." Kakar S.S. Eur. J. Endocrinol. 137:183-192(1997) [PubMed: 9272108] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[5]	"Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor." Grosse R., Schoneberg T., Schultz G., Gudermann T. Mol. Endocrinol. 11:1305-1318(1997) [PubMed: 9259321] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Pituitary.
[6]	"cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org)." Kopatz S.A., Aronstam R.S., Sharma S.V. Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Testis.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[8]	"Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene." Kottler M.L., Bergametti F., Carre M.C., Morice S., Decoret E., Lagarde J.P., Starzec A., Counis R. Eur. J. Endocrinol. 140:561-569(1999) [PubMed: 10366411] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 247-328 (ISOFORM 1).
[9]	"A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor." de Roux N., Young J., Misrahi M., Genet R., Chanson P., Schaison G., Milgrom E. N. Engl. J. Med. 337:1597-1602(1997) [PubMed: 9371856] [Abstract] Cited for: VARIANTS IHH ARG-106 AND GLN-262.
[10]	"Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism." Layman L.C., Cohen D.P., Jin M., Xie J., Li Z., Reindollar R.H., Bolbolan S., Bick D.P., Sherins R.R., Duck L.W., Musgrove L.C., Sellers J.C., Neill J.D. Nat. Genet. 18:14-15(1998) [PubMed: 9425890] [Abstract] Cited for: VARIANTS IHH GLN-262 AND CYS-284, CHARACTERIZATION OF VARIANTS IHH GLN-262 AND CYS-284.
[11]	"The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred." de Roux N., Young J., Brailly-Tabard S., Misrahi M., Milgrom E., Schaison G. J. Clin. Endocrinol. Metab. 84:567-572(1999) [PubMed: 10022417] [Abstract] Cited for: VARIANTS IHH ARG-106; ARG-217 AND GLN-262, CHARACTERIZATION OF VARIANTS IHH ARG-106; ARG-217 AND GLN-262.
[12]	"Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration." Caron P., Chauvin S., Christin-Maitre S., Bennet A., Lahlou N., Counis R., Bouchard P., Kottler M.-L. J. Clin. Endocrinol. Metab. 84:990-996(1999) [PubMed: 10084584] [Abstract] Cited for: VARIANTS IHH ASP-129 AND GLN-262, CHARACTERIZATION OF VARIANT IHH ASP-129.
[13]	"Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor." Pralong F.P., Gomez F., Castillo E., Cotecchia S., Abuin L., Aubert M.L., Portmann L., Gaillard R.C. J. Clin. Endocrinol. Metab. 84:3811-3816(1999) [PubMed: 10523035] [Abstract] Cited for: VARIANT IHH ARG-168, CHARACTERIZATION OF VARIANT IHH ARG-168.
[14]	"The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor." Pitteloud N., Boepple P.A., DeCruz S., Valkenburgh S.B., Crowley W.F. Jr., Hayes F.J. J. Clin. Endocrinol. Metab. 86:2470-2475(2001) [PubMed: 11397842] [Abstract] Cited for: VARIANT FEUNS ARG-106.
[15]	"A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene." Soederlund D., Canto P., de la Chesnaye E., Ulloa-Aguirre A., Mendez J.P. Clin. Endocrinol. (Oxf.) 54:493-498(2001) [PubMed: 11318785] [Abstract] Cited for: VARIANT IHH LYS-90.
[16]	"Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction." Costa E.M.F., Bedecarrats G.Y., Mendonca B.B., Arnhold I.J.P., Kaiser U.B., Latronico A.C. J. Clin. Endocrinol. Metab. 86:2680-2686(2001) [PubMed: 11397871] [Abstract] Cited for: VARIANTS IHH LYS-10; ARG-106 AND HIS-139, CHARACTERIZATION OF VARIANTS IHH LYS-10; ARG-106 AND HIS-139.
[17]	"Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site." Maya-Nunez G., Janovick J.A., Ulloa-Aguirre A., Soederlund D., Conn P.M., Mendez J.P. J. Clin. Endocrinol. Metab. 87:2144-2149(2002) [PubMed: 11994356] [Abstract] Cited for: CHARACTERIZATION OF VARIANT IHH LYS-90.
[18]	"Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism." Karges B., Karges W., Mine M., Ludwig L., Kuehne R., Milgrom E., de Roux N. J. Clin. Endocrinol. Metab. 88:1873-1879(2003) [PubMed: 12679486] [Abstract] Cited for: VARIANT IHH THR-171, CHARACTERIZATION OF VARIANT IHH THR-171.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	L03380 mRNA. Translation: AAA35918.1. L07949 mRNA. Translation: AAA35917.1. S60587 mRNA. Translation: AAB26287.1. S77472 mRNA. Translation: AAB33884.1. AF001952, AF001950, AF001951 Genomic DNA. Translation: AAB71348.1. Z81148 mRNA. Translation: CAB03541.1. AY392011 mRNA. Translation: AAR92228.1. BC113546 mRNA. Translation: AAI13547.1. Z99995 Genomic DNA. Translation: CAB17082.1.
IPI	IPI00028132. IPI00219387.
PIR	JC1353.
RefSeq	NP_000397.1. NM_000406.2. NP_001012781.1. NM_001012763.1.
UniGene	Hs.407587.
3D structure databases
ProteinModelPortal	P30968.
SMR	P30968. Positions 126-156.
ModBase	Search...
Protein-protein interaction databases
STRING	P30968.
Protein family/group databases
GPCRDB	Search...
Polymorphism databases
DMDM	399777.
Proteomic databases
PRIDE	P30968.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000226413; ENSP00000226413; ENSG00000109163.
GeneID	2798.
KEGG	hsa:2798.
UCSC	uc003hdm.1. human. uc003hdn.1. human.
Organism-specific databases
CTD	2798.
GeneCards	GC04M068608.
H-InvDB	HIX0031415.
HGNC	HGNC:4421. GNRHR.
MIM	138850. gene. 146110. phenotype. 228300. phenotype.
neXtProt	NX_P30968.
Orphanet	432. Normosmic congenital hypogonadotropic hypogonadism.
PharmGKB	PA28800.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG08564.
GeneTree	ENSGT00550000074198.
HOGENOM	HBG506082.
HOVERGEN	HBG009082.
InParanoid	P30968.
OMA	ATSFTVC.
OrthoDB	EOG4VT5XJ.
PhylomeDB	P30968.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	P30968.
Bgee	P30968.
CleanEx	HS_GNRHR.
Genevestigator	P30968.
GermOnline	ENSG00000109163. Homo sapiens.
Family and domain databases
InterPro	IPR000276. 7TM_GPCR_Rhodpsn. IPR017452. GPCR_Rhodpsn_supfam. IPR001658. GphnRH_rcpt. [Graphical view]
KO	K04280.
Pfam	PF00001. 7tm_1. 1 hit. [Graphical view]
PRINTS	PR00529. GNADOTRPHINR. PR00237. GPCRRHODOPSN.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. 1 hit. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
DrugBank	DB00106. Abarelix. DB00050. Cetrorelix. DB01406. Danazol. DB00644. Gonadorelin. DB00007. Leuprolide. DB00666. Nafarelin.
NextBio	11027.
SOURCE	Search...

Entry information

Entry name

GNRHR_HUMAN

Accession

Primary (citable) accession number: P30968
Secondary accession number(s): O75793, Q14D13, Q92644

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	July 1, 1993
Last modified:	January 25, 2012
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.