GnRH1 receptor

Target id: 256

Nomenclature: GnRH1 receptor

Family: Gonadotrophin-releasing hormone receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for GnRH1 receptor in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 328 4q21.2 GNRHR gonadotropin releasing hormone receptor 15,25-26,38,40,46,57
Mouse 7 327 5 E1 Gnrhr gonadotropin releasing hormone receptor 72,84
Rat 7 327 14p21 Gnrhr gonadotropin releasing hormone receptor 23,35,41,58,68
Previous and Unofficial Names
luteinizing hormone-releasing hormone (LHRH) receptor | GNRHR1 | LHRH receptor | Type I GnRHR | gnRH receptor | GnRH-R | GnRH I receptor | GnRHR | luliberin receptor | LHRHR
Database Links
Specialist databases
GPCRDB gnrhr_human (Hs), gnrhr_mouse (Mm), gnrhr_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
GnRH I {Sp: Human, Mouse, Rat}
GnRH II {Sp: Human}
Comments: GnRH I is the more potent agonist
Potency order of endogenous ligands (Human)
GnRH I (GNRH1, P01148) > GnRH II (GNRH2, O43555)  [54]

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
buserelin Hs Full agonist 9.5 – 10.4 pKd 59
pKd 9.5 – 10.4 (Kd 3x10-10 – 4x10-11 M) [59]
deslorelin Hs Full agonist 9.4 – 10.0 pKd 59
pKd 9.4 – 10.0 (Kd 4x10-10 – 1x10-10 M) [59]
histerelin Hs Full agonist 9.0 – 10.4 pKd 59
pKd 9.0 – 10.4 (Kd 1x10-9 – 4x10-11 M) [59]
alarelin Hs Full agonist 9.4 – 9.7 pKd 59
pKd 9.4 – 9.7 (Kd 4x10-10 – 2x10-10 M) [59]
[125I][des-Gly10,D-Ala6]GnRH N-ethylamide Hs Full agonist 9.3 pKd 1
pKd 9.3 [1]
[125I]triptorelin Rn Full agonist 9.3 pKd 20
pKd 9.3 [20]
fertirelin Hs Full agonist 9.1 – 9.1 pKd 59
pKd 9.1 – 9.1 (Kd 9x10-10 – 8x10-10 M) [59]
[125I][Tyr5,DAla6,NMeLeu7,Pro9-NEt]GnRH Hs Full agonist 8.5 pKd 69
pKd 8.5 [69]
GnRH III Hs Full agonist 8.2 pKd 52
pKd 8.2 (Kd 6.3x10-9 M) [52]
GnRH I {Sp: Human, Mouse, Rat} Hs Full agonist 7.7 – 8.5 pKd 59
pKd 7.7 – 8.5 (Kd 2.2x10-8 – 2.9x10-9 M) [59]
[125I]buserelin Rn Full agonist 7.4 pKd 42
pKd 7.4 (Kd 4x10-8 M) [42]
buserelin Hs Full agonist 9.4 – 10.0 pKi 59
pKi 9.4 – 10.0 (Ki 4x10-10 – 1x10-10 M) [59]
deslorelin Hs Full agonist 9.1 – 10.0 pKi 59
pKi 9.1 – 10.0 (Ki 8x10-10 – 1x10-10 M) [59]
triptorelin Hs Full agonist 9.3 – 9.5 pKi 6
pKi 9.3 – 9.5 (Ki 5.1x10-10 – 3.2x10-10 M) [6]
histerelin Hs Full agonist 8.7 – 9.7 pKi 59
pKi 8.7 – 9.7 (Ki 1.9x10-9 – 2x10-10 M) [59]
alarelin Hs Full agonist 9.1 – 9.3 pKi 59
pKi 9.1 – 9.3 (Ki 9x10-10 – 5x10-10 M) [59]
fertirelin Hs Full agonist 9.0 – 9.1 pKi 59
pKi 9.0 – 9.1 (Ki 1x10-9 – 7x10-10 M) [59]
leuprolide Hs Full agonist 8.5 – 9.1 pKi 80
pKi 8.5 – 9.1 (Ki 3.16x10-9 – 7.9x10-10 M) [80]
triptorelin Rn Full agonist 8.5 – 8.8 pKi 6
pKi 8.5 – 8.8 [6]
[His5,D-Tyr6]GnRH Hs Full agonist 7.8 – 8.4 pKi 80
pKi 7.8 – 8.4 [80]
GnRH I {Sp: Human, Mouse, Rat} Hs Full agonist 7.3 – 8.4 pKi 6,59,80
pKi 7.9 – 8.4 (Ki 1.3x10-8 – 4x10-9 M) [59]
pKi 7.3 – 8.4 [6,80]
GnRH I {Sp: Human, Mouse, Rat} Rn Full agonist 6.8 pKi 6
pKi 6.8 [6]
buserelin Hs Full agonist 10.5 pEC50 60
pEC50 10.5 (EC50 3x10-11 M) [60]
GnRH I {Sp: Human, Mouse, Rat} Hs Full agonist 10.0 pEC50 60
pEC50 10.0 (EC50 1x10-10 M) [60]
buserelin Mm Full agonist 9.3 – 10.1 pEC50 60
pEC50 9.3 – 10.1 (EC50 4.6x10-10 – 9x10-11 M) [60]
GnRH I {Sp: Human, Mouse, Rat} Mm Full agonist 7.8 – 7.9 pEC50 60
pEC50 7.8 – 7.9 (EC50 1.7x10-8 – 1.2x10-8 M) [60]
[des-Gly10,D-Ala6]GnRH N-ethylamide Mm Full agonist 9.9 pIC50 72
pIC50 9.9 [72]
leuprolide Rn Full agonist 9.1 pIC50 42
pIC50 9.1 [42]
GnRH I {Sp: Human, Mouse, Rat} Hs Full agonist 8.6 pIC50 49
pIC50 8.6 [49]
GnRH I {Sp: Human, Mouse, Rat} Mm Full agonist 8.3 pIC50 72
pIC50 8.3 [72]
GnRH I {Sp: Human, Mouse, Rat} Rn Full agonist 7.7 pIC50 42
pIC50 7.7 [42]
[D-Lys6]GnRH-II Hs Full agonist 7.6 pIC50 27
pIC50 7.6 (IC50 2.6x10-8 M) [27]
GnRH II {Sp: Human} Hs Full agonist 7.1 – 7.9 pIC50 27,49,79
pIC50 7.1 – 7.9 [27,49,79]
[Gln8]GnRH Hs Full agonist 7.1 pIC50 49
pIC50 7.1 [49]
[Trp8]GnRH Hs Full agonist 7.0 pIC50 49
pIC50 7.0 [49]
[Tyr8]GnRH Hs Full agonist 6.7 pIC50 49
pIC50 6.7 [49]
[Ser8]GnRH Hs Full agonist 6.2 pIC50 49
pIC50 6.2 [49]
[125I]GnRH I (human, mouse, rat) Hs Full agonist - -
goserelin Hs Full agonist - -
histrelin Hs Full agonist - -
nafarelin Hs Full agonist - -
View species-specific agonist tables
Agonist Comments
Although GnRH II has been shown to be present in several tissues in man, a full length GnRH II receptor transcript has not been identified, although it is present in other mammals. Thus, in man there is one functional receptor with two endogenous ligands that both have a high affinity for the receptor [54].

Several peptide agonist derivatives of GnRH are being used to design so-called bioconjugates, where the peptide is used as a targeting moiety and a chemotherapeutic agent is coupled for the cytotoxic effect (for reviews see [48] and [77]).

The receptor binding kinetics (i.e. association rate and dissociation rates) of some peptide agonists have also been determined in Nederpelt et al., 2016 [59].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[125I]cetrorelix Hs Antagonist 9.7 pKd 33
pKd 9.7 [33]
[3H]NBI-49202 Hs Antagonist 9.7 pKd 82
pKd 9.7 [82]
D-23487 Hs Antagonist 10.0 pKi 8
pKi 10.0 [8]
sufugolix Hs Antagonist 10.0 pKi 76
pKi 10.0 [76]
cetrorelix Hs Antagonist 9.3 – 10.0 pKi 7-8,80
pKi 9.3 – 10.0 [7-8,80]
antarelix Hs Antagonist 9.6 pKi 8
pKi 9.6 [8]
iturelix Hs Antagonist 9.5 pKi 73
pKi 9.5 (Ki 3.5x10-10 M) [73]
abarelix Hs Antagonist 9.1 – 9.5 pKi 80
pKi 9.1 – 9.5 (Ki 7.9x10-10 – 3.2x10-10 M) [80]
NBI-42902 Hs Antagonist 9.0 – 9.5 pKi 80
pKi 9.1 – 9.5 [80]
pKi 9.0 – 9.3 [80]
elagolix Hs Antagonist 9.1 pKi 11
pKi 9.1 (Ki 9x10-10 M) [11]
degarelix Hs Antagonist 8.8 pKi 86
pKi 8.8 (Ki 1.7x10-9 M) [86]
D-24710 Hs Antagonist 8.6 pKi 8
pKi 8.6 [8]
FD-1 Hs Antagonist 8.3 pKi 31
pKi 8.3 [31]
CMPD-1 Hs Antagonist 8.2 pKi 1
pKi 8.2 [1]
cyclorelix Hs Antagonist 7.9 pKi 8
pKi 7.9 [8]
T-98475 Hs Antagonist 9.7 pIC50 16
pIC50 9.7 [16]
TAK-385 Hs Antagonist 9.5 pIC50 56
pIC50 9.5 (IC50 3.3x10-10 M) [56]
TAK-385 Rn Antagonist 9.5 pIC50 56
pIC50 9.5 (IC50 3.3x10-10 M) [56]
IN-3 Hs Antagonist 9.2 pIC50 5,34
pIC50 9.2 (IC50 6x10-10 M) [5,34]
[Ac-D-2Nal1,D4CPA2,D-3Pal3,6,Leu8, D-Ala10]GnRH-II Hs Antagonist 9.2 pIC50 27
pIC50 9.2 (IC50 6.6x10-10 M) [27]
iturelix Hs Antagonist 9.0 pIC50 61
pIC50 9.0 (IC50 1.05x10-9 M) [61]
IN-3 Rn Antagonist 8.8 pIC50 5
pIC50 8.8 (IC50 1.7x10-9 M) [5]
cetrorelix Hs Antagonist 8.7 pIC50 61
pIC50 8.7 (IC50 1.98x10-9 M) [61]
WAY-207024 Hs Antagonist 7.9 pIC50 66
pIC50 7.9 (IC50 1.2x10-8 M) [66]
WAY-207024 Rn Antagonist 7.2 pIC50 66
pIC50 7.2 (IC50 7.1x10-8 M) [66]
View species-specific antagonist tables
Antagonist Comments
In addition, non-peptide GnRH receptor antagonists have been reviewed recently [9,30]

The GnRH-I receptor has been shown to be highly sensitive polymorphisms, which often result in lower plasma membrane expression due to retention or degredation in the ER. Hence, so-called pharmacochaperones are being developed for this receptor. Some GnRH receptor antagonists have been reported as pharmacochaperons, e.g. IN3 and TAK-013 (for review see [18])

SKI2670 (undisclosed structure) a novel, orally active, non-peptide GnRH antagonist has a demonstrated binding affinity of IC50=0.25 nM (pIC50=9.6) in human [39].

Note: Antarelix is sometimes refered to as Teverelix, and TAK-385 is now named Relugolix.

There are some novel developments with regard to small molecule GnRH receptor antagonists:
- designed as tracer ligand for PET studies in vivo in rats [63]
- conjugated with cytotoxic agents, e.g. Paclitaxel-degarelix [87]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CMPD-1 Hs Negative 7.8 pIC50 81
pIC50 7.8 [81]
FD-1 Hs Negative 5.3 pIC50 31
pIC50 5.3 [31]
5-(N,N-hexamethylene)-amiloride Hs Negative 4.3 pIC50 31
pIC50 4.3 [31]
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  70,78
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Other - See Comments
Comments:  GnRH receptor coupling to Gi has been demonstrated in several cancer cells, but also in rat pituitary cells.
References:  54
Tissue Distribution
Pituitary.
Species:  Human
Technique:  Immunohistochemistry.
References:  43
Pituitary.
Species:  Human
Technique:  RT-PCR.
References:  55,75
Ovary: granulosa-luteal cells.
Species:  Human
Technique:  RT-PCR.
References:  67
Pituitary, breast, ovary, prostate.
Species:  Human
Technique:  RT-PCR.
References:  36
Liver, heart, skeletal muscle, kidney, placenta, pituitary.
Species:  Human
Technique:  RT-PCR.
References:  37
Peripheral blood mononuclear cells.
Species:  Human
Technique:  RT-PCR.
References:  12
Sperm, anterior pituitary.
Species:  Human
Technique:  Immunohistochemistry.
References:  45
Heart (cardiomyocytes)
Species:  Mouse
Technique:  Ca2+ release in cardiomyocytes
References:  22
Heart (cardiomyocytes)
Species:  Mouse
Technique:  Cardiomyocyte contractility
References:  22
Anterior pituitary, ovary.
Species:  Rat
Technique:  Radioligand binding.
References:  71
Prostate.
Species:  Rat
Technique:  RT-PCR.
References:  44
Pituitary.
Species:  Rat
Technique:  Radioligand binding.
References:  17,19,28,50
Mammary gland.
Species:  Rat
Technique:  RT-PCR.
References:  47
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Inhibition of LH release from primary rat pituitary cells
Species:  Rat
Tissue:  Pituitary cells
Response measured:  LH release
References:  65
cAMP production
Species:  Mouse
Tissue:  L-beta-T2 gonadotrope cells
Response measured:  Activation
References:  85
Effect on cardiomyocyte contraction
Species:  Mouse
Tissue:  Heart (cardiomyocytes)
Response measured:  Cardiomyocyte contraction
References:  22
Measurement of Ca2+ in Xenopus oocytes transfected with the mouse GnRH receptor.
Species:  Mouse
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of calcium mobilisation.
References:  72
Ca2+ release in cardiomyocytes
Species:  Mouse
Tissue:  Heart (cardiomyocytes)
Response measured:  Ca2+ release
References:  22
Measurement of IP levels in COS-M6 cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  COS-M6 cells.
Response measured:  Stimulation of IP accumulation.
References:  68
Measurement of IP levels in HEK 293 cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  Stimulation of IP accumulation.
References:  3,29
Measurement of Ca2+ levels in mouse pituitary gonadotrope alpha T3-1 cells endogenously expressing the GnRH receptor.
Species:  Mouse
Tissue:  T3-1 cells.
Response measured:  Stimulation of calcium mobilisation.
References:  3-4
Measurement of IP levels in mouse pituitary gonadotrope alpha T3-1 cells endogenously expressing the GnRH receptor.
Species:  Mouse
Tissue:  T3-1 cells.
Response measured:  Stimulation of IP accumulation.
References:  3-4,70,78
Measurement of Ca2+ levels in HEK 293 cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  Stimulation of calcium mobilisation.
References:  3
Measurement of IP levels in immature and mature rat ovarian granulosa cells endogenously expressing the GnRH receptor.
Species:  Rat
Tissue:  Ovarian granulosa cells.
Response measured:  Stimulation of IP accumulation.
References:  2
Measurement of in Ca2+ levels in immature and mature rat ovarian granulosa cells endogenously expressing the GnRH receptor.
Species:  Rat
Tissue:  Ovarian granulosa cells.
Response measured:  Stimulation of calcium mobilisation.
References:  2
Measurement of arachidonic acid release from mouse pituitary gonadotrope alpha T3-1 cells endogenously expressing the GnRH receptor.
Species:  Mouse
Tissue:  T3-1 cells.
Response measured:  Stimulation of arachidonic acid production.
References:  70
Measurement of phosphatidylethanol (PEt) in mouse pituitary gonadotrope alpha T3-1 cells endogenously expressing the GnRH receptor.
Species:  Mouse
Tissue:  T3-1 cells.
Response measured:  Stimulation of PEt production.
References:  62,70
Measurement of IP levels in COS-7 cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  COS-7 cells.
Response measured:  Stimulation of IP accumulation.
References:  29
Measurement of IP levels in COS-M6 cells transfected with the mouse GnRH receptor.
Species:  Mouse
Tissue:  COS-M6 cells.
Response measured:  Stimulation of IP accumulation.
References:  68
Measurement of prolactin release from GH3 cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  GGH3-1' cells.
Response measured:  Prolactin release by a cAMP-dependent mechanism.
References:  42
Measurement of IP levels in Sf9 insect cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  Sf9 cells.
Response measured:  Stimulation of IP accumulation.
References:  20
Measurement of cAMP levels in Sf9 insect cells transfected with the rat GnRH receptor.
Species:  Rat
Tissue:  Sf9 cells.
Response measured:  Stimulation of cAMP accumulation.
References:  20
Measurement of IP levels in CHO cells transfected with the human GnRH receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Stimulation of IP accumulation.
References:  21
Measurement of arachidonic acid release from CHO cells transfected with the human GnRH receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Stimulation of arachidonic acid production.
References:  76
Measurement of IP levels in RBL cells transfected with the human GnRH receptor.
Species:  Human
Tissue:  RBL cells.
Response measured:  Stimulation of IP accumulation.
References:  81
hERG potassium channel
Species:  Mouse
Tissue:  Gonadotrophs
Response measured:  Inhibition
References:  32
Inhibition of ovarian cancer cell proliferation
Species:  Human
Tissue:  Human ovarian cancer cell lines (OVCAR3 and CAOV4)
Response measured:  Cell number/proliferation
References:  74
Inhibition of breast cancer cell proliferation
Species:  Human
Tissue:  Human breast cancer cell lines (T47D and SKBR3)
Response measured:  Cell number/proliferation
References:  74
Effect on growth of human ovarian cancer cells.
Species:  Human
Tissue:  A2780, Acis2780, Ovcar-3 or SKOV-3 cells.
Response measured:  Inhibition of cell growth.
References:  24
Effect on cell migration of ovarian cancer cells.
Species:  Human
Tissue:  ES-2 cells.
Response measured:  Cell migration.
References:  83
Effect on cell migration or cell invasion of endometrial cancer cells.
Species:  Human
Tissue:  Ishikawa or ECC-1 cells.
Response measured:  Cell migration or invasion.
References:  88
Impedance-based real-time measurement of cell morphology.
Species:  Human
Tissue:  CHOhGnRH cells
Response measured:  Changes in impedance induced by changes in cell morphology.
References:  60
Impedance-based real-time measurement of cell morphology.
Species:  Mouse
Tissue:  αT3-1 cells
Response measured:  Changes in impedance induced by changes in cell morphology.
References:  60
Effect on growth of human endometrial cancer cells.
Species:  Human
Tissue:  Hec1A, Ishikawa and OAW-42 cells.
Response measured:  Inhibition of cell growth.
References:  24
Physiological Functions
Gonadotropin synthesis and secretion.
Species:  Human
Tissue:  Pituitary.
References:  13
Ovarian steroidogenesis.
Species:  Human
Tissue:  Ovary.
References:  13
Cell proliferation.
Species:  Human
Tissue:  Malignant tumours.
References:  13
Apoptosis.
Species:  Human
Tissue:  Ovarian granulosa cells.
References:  13
Physiological Consequences of Altering Gene Expression
Mutant mice with inactive GnRH receptors exhibit a deficiency in LH, follicle-stimulating hormone and gonadal steroids. In addition, there is failure of the sex organs to develop postnatally, resulting in small, undescended testes that are located in the low abdominal position as well as poor differentiation of Leydig cells.
Species:  Mouse
Tissue: 
Technique:  Induced mutation.
References:  51,64
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005189 abnormal anogenital distance PMID: 15625238 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005418 abnormal circulating hormone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0009199 abnormal external male genitalia morphology PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001119 abnormal female reproductive system morphology PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0003699 abnormal female reproductive system physiology PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0009209 abnormal internal female genitalia morphology PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0009205 abnormal internal male genitalia morphology PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001145 abnormal male reproductive system morphology PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001126 abnormal ovary morphology PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0009363 abnormal secondary ovarian follicle morphology PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002216 abnormal seminiferous tubule morphology PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0006379 abnormal spermatocyte morphology PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001146 abnormal testis morphology PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001134 absent corpus luteum PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0009009 absent estrous cycle PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0008261 arrest of male meiosis PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001143 constricted vagina opening PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0002286 cryptorchism PMID: 15625238 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0003510 decreased circulating dihydrotestosterone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0005181 decreased circulating estradiol level PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0002790 decreased circulating follicle stimulating hormone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002790 decreased circulating follicle stimulating hormone level PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002773 decreased circulating luteinizing hormone level PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005185 decreased circulating progesterone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0005185 decreased circulating progesterone level PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0002780 decreased circulating testosterone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002780 decreased circulating testosterone level PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005130 decreased follicle stimulating hormone level PMID: 15625238 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005132 decreased luteinizing hormone level PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0004856 decreased ovary weight PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0004852 decreased testis weight PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0004852 decreased testis weight PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0002636 delayed vaginal opening PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002636 delayed vaginal opening PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001926 female infertility PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001129 impaired ovarian folliculogenesis PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001129 impaired ovarian folliculogenesis PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001260 increased body weight PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001925 male infertility PMID: 20068010 
Gnrhrtm1(cre)Uboe Gnrhrtm1(cre)Uboe/?
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002169 no abnormal phenotype detected PMID: 18325995 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0004930 small epididymis PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0004930 small epididymis PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001116 small gonad PMID: 15625238 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001127 small ovary PMID: 15625238 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0005188 small penis PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0005188 small penis PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0002716 small preputial glands PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001157 small seminal vesicle PMID: 15625238 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001157 small seminal vesicle PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001153 small seminiferous tubules PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0001147 small testis PMID: 20068010 
GnrhrGt(CMHD-GT_181A6-3)Cmhd GnrhrGt(CMHD-GT_181A6-3)Cmhd/GnrhrGt(CMHD-GT_181A6-3)Cmhd
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:95790  MP:0009081 thin uterus PMID: 20068010 
Gnrhrhh Gnrhrhh/Gnrhrhh
involves: 129S6/SvEvTac * C57BL/6
MGI:95790  MP:0001121 uterus hypoplasia PMID: 15625238 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Fertile eunuch syndrome
OMIM: 228300
Orphanet: ORPHA432
Disease:  Hypogonadotropic hypogonadism 7 with or without anosmia; HH7
Synonyms: Idiopathic hypogonadotropic hypogonadism
Isolated hypogonadotropic hypogonadism
OMIM: 146110
Orphanet: ORPHA432
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human N10K 14
Missense Human T32I 14
Missense Human Q106R 14
Missense Human A129D 14
Missense Human A171T 14
Missense Human C200Y 14
Missense Human R262Q 14
Missense Human L266R 14
Missense Human Y284C 14
Disease:  Normosmic congenital hypogonadotropic hypogonadism
Orphanet: ORPHA432
Comments: 
References:  10
Clinically-Relevant Mutations and Pathophysiology Comments
Many more somatic mutations have been described. It remains a challenge to link the severity of the gonadotropic deficiency to the genotype.
General Comments
The mammalian GnRH receptor is the only GPCR in which the intracellular C-terminal tail is completely absent. Unlike other GPCRs, it does not show rapid desensitisation of IP production and the rate of internalisation is low. The addition of a functional intracellular C-terminal tail to the receptor produces rapid desinsitisation and increases internalisation rates [29].

For a review on GnRH and the GnRH receptor see [53].

References

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1. Anderes KL, Luthin DR, Castillo R, Kraynov EA, Castro M, Nared-Hood K, Gregory ML, Pathak VP, Christie LC, Paderes G, Vazir H, Ye Q, Anderson MB, May JM. (2003) Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats. J Pharmacol Exp Ther305: 688-695. [PMID:12606616]

2. Anderson L, Hillier SG, Eidne KA, Miro F. (1996) GnRH-induced calcium mobilisation and inositol phosphate production in immature and mature rat ovarian granulosa cells. J Endocrinol149: 449-456. [PMID:8691103]

3. Anderson L, McGregor A, Cook JV, Chilvers E, Eidne KA. (1995) Rapid desensitization of GnRH-stimulated intracellular signalling events in alpha T3-1 and HEK-293 cells expressing the GnRH receptor. Endocrinology136: 5228-5231. [PMID:7588262]

4. Anderson L, Milligan G, Eidne KA. (1993) Characterization of the gonadotrophin-releasing hormone receptor in alpha T3-1 pituitary gonadotroph cells. J Endocrinol136: 51-58. [PMID:8381456]

5. Ashton WT, Sisco RM, Kieczykowski GR, Yang YT, Yudkovitz JB, Cui J, Mount GR, Ren RN, Wu TJ, Shen X et al.. (2001) Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity. Bioorg. Med. Chem. Lett.11 (19): 2597-602. [PMID:11551758]

6. Beckers T, Bernd M, Kutscher B, Kühne R, Hoffmann S, Reissmann T. (2001) Structure-function studies of linear and cyclized peptide antagonists of the GnRH receptor. Biochem Biophys Res Commun289: 653-663. [PMID:11726197]

7. Beckers T, Marheineke K, Reiländer H, Hilgard P. (1995) Selection and characterization of mammalian cell lines with stable over-expression of human pituitary receptors for gonadoliberin. Eur J Biochem231: 535-543. [PMID:7649152]

8. Beckers T, Reiländer H, Hilgard P. (1997) Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay. Anal Biochem251: 17-23. [PMID:9300077]

9. Betz SF, Zhu YF, Chen C, Struthers RS. (2008) Non-peptide gonadotropin-releasing hormone receptor antagonists. J Med Chem51: 3331-3348. [PMID:18419112]

10. Bédécarrats GY, Kaiser UB. (2007) Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function. Semin Reprod Med25: 368-378. [PMID:17710733]

11. Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M et al.. (2008) Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J. Med. Chem.51 (23): 7478-85. [PMID:19006286]

12. Chen HF, Jeung EB, Stephenson M, Leung PC. (1999) Human peripheral blood mononuclear cells express gonadotropin-releasing hormone (GnRH), GnRH receptor, and interleukin-2 receptor gamma-chain messenger ribonucleic acids that are regulated by GnRH in vitro. J Clin Endocrinol Metab84: 743-750. [PMID:10022447]

13. Cheng CK, Leung PC. (2005) Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev26: 283-306. [PMID:15561800]

14. Chevrier L, Guimiot F, de Roux N. (2011) GnRH receptor mutations in isolated gonadotropic deficiency. Mol. Cell. Endocrinol.346 (1-2): 21-8. [PMID:21645587]

15. Chi L, Zhou W, Prikhozhan A, Flanagan C, Davidson JS, Golembo M, Illing N, Millar RP, Sealfon SC. (1993) Cloning and characterization of the human GnRH receptor. Mol Cell Endocrinol91: R1-R6. [PMID:8386108]

16. Cho N, Harada M, Imaeda T, Imada T, Matsumoto H, Hayase Y, Sasaki S, Furuya S, Suzuki N, Okubo S, Ogi K, Endo S, Onda H, Fujino M. (1998) Discovery of a novel, potent, and orally active nonpeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor. J Med Chem41: 4190-4195. [PMID:9784092]

17. Clayton RN, Solano AR, Garcia-Vela A, Dufau ML, Catt KJ. (1980) Regulation of pituitary receptors for gonadotropin-releasing hormone during the rat estrous cycle. Endocrinology107: 699-706. [PMID:6249571]

18. Conn PM, Ulloa-Aguirre A. (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv. Pharmacol.62: 109-41. [PMID:21907908]

19. Conne BS, Scaglioni S, Lang U, Sizonenko PC, Aubert ML. (1982) Pituitary receptor sites for gonadotropin-releasing hormone: effect of castration and substitutive therapy with sex steroids in the male rat. Endocrinology110: 70-79. [PMID:6274626]

20. Delahaye R, Manna PR, Bérault A, Berreur-Bonnenfant J, Berreur P, Counis R. (1997) Rat gonadotropin-releasing hormone receptor expressed in insect cells induces activation of adenylyl cyclase. Mol Cell Endocrinol135: 119-127. [PMID:9484907]

21. DeVita RJ, Walsh TF, Young JR, Jiang J, Ujjainwalla F, Toupence RB, Parikh M, Huang SX, Fair JA, Goulet MT, Wyvratt MJ, Lo JL, Ren N, Yudkovitz JB, Yang YT, Cheng K, Cui J, Mount G, Rohrer SP, Schaeffer JM, Rhodes L, Drisko JE, McGowan E, MacIntyre DE, Vincent S, Carlin JR, Cameron J, Smith RG. (2001) A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor. J Med Chem44: 917-922. [PMID:11300873]

22. Dong F, Skinner DC, Wu TJ, Ren J. (2011) The heart: a novel gonadotrophin-releasing hormone target. J. Neuroendocrinol.23 (5): 456-63. [PMID:21332841]

23. Eidne KA, Sellar RE, Couper G, Anderson L, Taylor PL. (1992) Molecular cloning and characterisation of the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Mol Cell Endocrinol90: R5-R9. [PMID:1338727]

24. Engel JB, Hahne JC, Häusler SF, Meyer S, Segerer SE, Diessner J, Dietl J, Honig A. (2012) Peptidomimetic GnRH antagonist AEZS-115 inhibits the growth of ovarian and endometrial cancer cells. Anticancer Res.32 (5): 2063-8. [PMID:22593489]

25. Fan NC, Jeung EB, Peng C, Olofsson JI, Krisinger J, Leung PC. (1994) The human gonadotropin-releasing hormone (GnRH) receptor gene: cloning, genomic organization and chromosomal assignment. Mol Cell Endocrinol103: R1-R6. [PMID:7958384]

26. Fan NC, Peng C, Krisinger J, Leung PC. (1995) The human gonadotropin-releasing hormone receptor gene: complete structure including multiple promoters, transcription initiation sites, and polyadenylation signals. Mol Cell Endocrinol107: R1-R8. [PMID:7768323]

27. Fister S, Günthert AR, Aicher B, Paulini KW, Emons G, Gründker C. (2009) GnRH-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein Bax. Cancer Res.69 (16): 6473-81. [PMID:19638591]

28. Halmos G, Schally AV. (2002) Changes in subcellular distribution of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) after treatment with the LH-RH antagonist cetrorelix. Proc Natl Acad Sci U S A99: 961-965. [PMID:11805337]

29. Heding A, Vrecl M, Bogerd J, McGregor A, Sellar R, Taylor PL, Eidne KA. (1998) Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics. J Biol Chem273: 11472-11477. [PMID:9565559]

30. Heitman LH, Ijzerman AP. (2008) G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands. Med Res Rev28: 975-1011. [PMID:18561294]

31. Heitman LH, Ye K, Oosterom J, Ijzerman AP. (2008) Amiloride derivatives and a nonpeptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing hormone receptor. Mol Pharmacol73: 1808-1815. [PMID:18344315]

32. Hirdes W, Dinu C, Bauer CK, Boehm U, Schwarz JR. (2010) Gonadotropin-releasing hormone inhibits ether-à-go-go-related gene K+ currents in mouse gonadotropes. Endocrinology151 (3): 1079-88. [PMID:20068004]

33. Hoffmann SH, ter Laak T, Kühne R, Reiländer H, Beckers T. (2000) Residues within transmembrane helices 2 and 5 of the human gonadotropin-releasing hormone receptor contribute to agonist and antagonist binding. Mol Endocrinol14: 1099-1115. [PMID:10894158]

34. Janovick JA, Maya-Nunez G, Conn PM. (2002) Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. J. Clin. Endocrinol. Metab.87 (7): 3255-62. [PMID:12107234]

35. Kaiser UB, Zhao D, Cardona GR, Chin WW. (1992) Isolation and characterization of cDNAs encoding the rat pituitary gonadotropin-releasing hormone receptor. Biochem Biophys Res Commun189: 1645-1652. [PMID:1339279]

36. Kakar SS, Grizzle WE, Neill JD. (1994) The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. Mol Cell Endocrinol106: 145-149. [PMID:7534732]

37. Kakar SS, Jennes L. (1995) Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues. Cancer Lett98: 57-62. [PMID:8529206]

38. Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD. (1992) Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem Biophys Res Commun189: 289-295. [PMID:1333190]

39. Kim SM, Yoo T, Lee SY, Kim EJ, Lee SM, Lee MH, Han MY, Jung SH, Choi JH, Ryu KH et al.. (2015) Effect of SKI2670, a novel, orally active, non-peptide GnRH antagonist, on hypothalamic-pituitary-gonadal axis. Life Sci.139: 166-74. [PMID:26321528]

40. Kottler ML, Lorenzo F, Bergametti F, Commerçon P, Souchier C, Counis R. (1995) Subregional mapping of the human gonadotropin-releasing hormone receptor (GnRH-R) gene to 4q between the markers D4S392 and D4S409. Hum Genet96: 477-480. [PMID:7557974]

41. Kudo A, Park MK, Kawashima S. (1993) Isolation of rat GnRH receptor cDNA having different 5'-noncoding sequence. Zoolog Sci10: 863-867. [PMID:7764374]

42. Kuphal D, Janovick JA, Kaiser UB, Chin WW, Conn PM. (1994) Stable transfection of GH3 cells with rat gonadotropin-releasing hormone receptor complementary deoxyribonucleic acid results in expression of a receptor coupled to cyclic adenosine 3',5'-monophosphate-dependent prolactin release via a G-protein. Endocrinology135: 315-320. [PMID:8013367]

43. La Rosa S, Celato N, Uccella S, Capella C. (2000) Detection of gonadotropin-releasing hormone receptor in normal human pituitary cells and pituitary adenomas using immunohistochemistry. Virchows Arch437: 264-269. [PMID:11037346]

44. Lau HL, Zhu XM, Leung PC, Chan LW, Chen GF, Chan PS, Yu KL, Chan FL. (2001) Detection of mRNA expression of gonadotropin-releasing hormone and its receptor in normal and neoplastic rat prostates. Int J Oncol19: 1193-1201. [PMID:11713589]

45. Lee CY, Ho J, Chow SN, Yasojima K, Schwab C, McGeer PL. (2000) Immunoidentification of gonadotropin releasing hormone receptor in human sperm, pituitary and cancer cells. Am J Reprod Immunol44: 170-177. [PMID:11028904]

46. Leung PC, Squire J, Peng C, Fan N, Hayden MR, Olofsson JI. (1995) Mapping of the gonadotropin-releasing hormone (GnRH) receptor gene to human chromosome 4q21.2 by fluorescence in situ hybridization. Mamm Genome6: 309-310. [PMID:7613048]

47. Levi LN, Ben-Aroya N, Tel-Or S, Palmon A, Burstein Y, Koch Y. (1996) Expression of the gene for the receptor of gonadotropin-releasing hormone in the rat mammary gland. FEBS Lett379: 186-190. [PMID:8635589]

48. Liu SV, Liu S, Pinski J. (2011) Luteinizing hormone-releasing hormone receptor targeted agents for prostate cancer. Expert Opin Investig Drugs20 (6): 769-78. [PMID:21449823]

49. Lu ZL, Coetsee M, White CD, Millar RP. (2007) Structural determinants for ligand-receptor conformational selection in a peptide G protein-coupled receptor. J Biol Chem282: 17921-17929. [PMID:17452338]

50. Marian J, Conn PM. (1983) Subcellular localization of the receptor for gonadotropin-releasing hormone in pituitary and ovarian tissue. Endocrinology112: 104-112. [PMID:6291912]

51. Mason AJ, Hayflick JS, Zoeller RT, Young WS, Phillips HS, Nikolics K, Seeburg PH. (1986) A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse. Science234: 1366-1371. [PMID:3024317]

52. Mezo G, Czajlik A, Manea M, Jakab A, Farkas V, Majer Z, Vass E, Bodor A, Kapuvári B, Boldizsár M et al.. (2007) Structure, enzymatic stability and antitumor activity of sea lamprey GnRH-III and its dimer derivatives. Peptides28 (4): 806-20. [PMID:17254668]

53. Millar RP. (2005) GnRHs and GnRH receptors. Anim Reprod Sci88: 5-28. [PMID:16140177]

54. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. (2004) Gonadotropin-releasing hormone receptors. Endocr Rev25: 235-275. [PMID:15082521]

55. Miller GM, Alexander JM, Klibanski A. (1996) Gonadotropin-releasing hormone messenger RNA expression in gonadotroph tumors and normal human pituitary. J Clin Endocrinol Metab81: 80-83. [PMID:8550798]

56. Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S et al.. (2011) Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. J. Med. Chem.54 (14): 4998-5012. [PMID:21657270]

57. Morrison N, Sellar RE, Boyd E, Eidne KA, Connor JM. (1994) Assignment of the gene encoding the human gonadotropin-releasing hormone receptor to 4q13.2-13.3 by fluorescence in situ hybridization. Hum Genet93: 714-715. [PMID:8005601]

58. Naor Z, Clayton RN, Catt KJ. (1980) Characterization of gonadotropin-releasing hormone receptors in cultured rat pituitary cells. Endocrinology107: 1144-1152. [PMID:6250793]

59. Nederpelt I, Georgi V, Schiele F, Nowak-Reppel K, Fernández-Montalván AE, IJzerman AP, Heitman LH. (2016) Characterization of 12 GnRH peptide agonists - a kinetic perspective. Br. J. Pharmacol.173 (1): 128-41. [PMID:26398856]

60. Nederpelt I, Vergroesen RD, IJzerman AP, Heitman LH. (2016) Persistent GnRH receptor activation in pituitary αT3-1 cells analyzed with a label-free technology. Biosens Bioelectron79: 721-7. [PMID:26774084]

61. Neill JD. (2002) GnRH and GnRH receptor genes in the human genome. Endocrinology143 (3): 737-43. [PMID:11861490]

62. Netiv E, Liscovitch M, Naor Z. (1991) Delayed activation of phospholipase D by gonadotropin-releasing hormone in a clonal pituitary gonadotrope cell line (alpha T3-1). FEBS Lett295: 107-109. [PMID:1765140]

63. Olberg DE, Bauer N, Andressen KW, Hjørnevik T, Cumming P, Levy FO, Klaveness J, Haraldsen I, Sutcliffe JL. (2016) Brain penetrant small molecule (18)F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. Nucl. Med. Biol.43 (8): 478-89. [PMID:27236283]

64. Pask AJ, Kanasaki H, Kaiser UB, Conn PM, Janovick JA, Stockton DW, Hess DL, Justice MJ, Behringer RR. (2005) A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Mol Endocrinol19: 972-981. [PMID:15625238]

65. Pelletier JC, Chengalvala M, Cottom J, Feingold I, Garrick L, Green D, Hauze D, Huselton C, Jetter J, Kao W et al.. (2008) 2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor. Bioorg. Med. Chem.16 (13): 6617-40. [PMID:18511284]

66. Pelletier JC, Chengalvala MV, Cottom JE, Feingold IB, Green DM, Hauze DB, Huselton CA, Jetter JW, Kopf GS, Lundquist JT et al.. (2009) Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R). J. Med. Chem.52 (7): 2148-52. [PMID:19271735]

67. Peng C, Fan NC, Ligier M, Väänänen J, Leung PC. (1994) Expression and regulation of gonadotropin-releasing hormone (GnRH) and GnRH receptor messenger ribonucleic acids in human granulosa-luteal cells. Endocrinology135: 1740-1746. [PMID:7956897]

68. Perrin MH, Bilezikjian LM, Hoeger C, Donaldson CJ, Rivier J, Haas Y, Vale WW. (1993) Molecular and functional characterization of GnRH receptors cloned from rat pituitary and a mouse pituitary tumor cell line. Biochem Biophys Res Commun191: 1139-1144. [PMID:7916600]

69. Perrin MH, Haas Y, Rivier JE, Vale WW. (1983) Gonadotropin-releasing hormone binding to rat anterior pituitary membrane homogenates. Comparison of antagonists and agonists using radiolabeled antagonist and agonist. Mol Pharmacol23: 44-51. [PMID:6346049]

70. Poulin B, Rich N, Mitev Y, Gautron JP, Kordon C, Enjalbert A, Drouva SV. (1996) Differential involvement of calcium channels and protein kinase-C activity in GnRH-induced phospholipase-C, -A2 and -D activation in a gonadotrope cell line (alpha T3-1). Mol Cell Endocrinol122: 33-50. [PMID:8898346]

71. Reeves JJ, Séguin C, Lefebvre FA, Kelly PA, Labrie F. (1980) Similar luteinizing hormone-releasing hormone binding sites in rat anterior pituitary and ovary. Proc Natl Acad Sci U S A77: 5567-5571. [PMID:6254091]

72. Reinhart J, Mertz LM, Catt KJ. (1992) Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor. J Biol Chem267: 21281-21284. [PMID:1328228]

73. Rivier J, Theobald P, Porter J, Perrin M, Gunnet J, Hahn DW, Rivier C. (1991) Gonadotropin releasing hormone antagonists: novel structures incorporating N omega-cyano modified guanidine moieties. Biochem. Biophys. Res. Commun.176 (1): 406-12. [PMID:1850267]

74. Saleh-Abady MM, Naderi-Manesh H, Alizadeh A, Shamsipour F, Balalaie S, Arabanian A. (2010) Anticancer activity of a new gonadotropin releasing hormone analogue. Biopolymers94 (3): 292-7. [PMID:19908246]

75. Sanno N, Jin L, Qian X, Osamura RY, Scheithauer BW, Kovacs K, Lloyd RV. (1997) Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor messenger ribonucleic acids expression in nontumorous and neoplastic pituitaries. J Clin Endocrinol Metab82: 1974-1982. [PMID:9177416]

76. Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M. (2003) Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J Med Chem46: 113-124. [PMID:12502365]

77. Schally AV, Engel JB, Emons G, Block NL, Pinski J. (2011) Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors. Curr Drug Deliv8 (1): 11-25. [PMID:21034424]

78. Shah BH, Milligan G. (1994) The gonadotrophin-releasing hormone receptor of alpha T3-1 pituitary cells regulates cellular levels of both of the phosphoinositidase C-linked G proteins, Gq alpha and G11 alpha, equally. Mol Pharmacol46: 1-7. [PMID:8058044]

79. Stewart AJ, Sellar R, Wilson DJ, Millar RP, Lu ZL. (2008) Identification of a novel ligand binding residue Arg38(1.35) in the human gonadotropin-releasing hormone receptor. Mol Pharmacol73: 75-81. [PMID:17942747]

80. Struthers RS, Xie Q, Sullivan SK, Reinhart GJ, Kohout TA, Zhu YF, Chen C, Liu XJ, Ling N, Yang W, Maki RA, Bonneville AK, Chen TK, Bozigian HP. (2007) Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902. Endocrinology148: 857-867. [PMID:17095587]

81. Sullivan SK, Brown MS, Gao Y, Loweth CJ, Lio FM, Crowe PD, Struthers RS, Betz SF. (2006) Allosteric and orthosteric binding modes of two nonpeptide human gonadotropin-releasing hormone receptor antagonists. Biochemistry45: 15327-15337. [PMID:17176055]

82. Sullivan SK, Hoare SR, Fleck BA, Zhu YF, Heise CE, Struthers RS, Crowe PD. (2006) Kinetics of nonpeptide antagonist binding to the human gonadotropin-releasing hormone receptor: Implications for structure-activity relationships and insurmountable antagonism. Biochem Pharmacol72: 838-849. [PMID:16930559]

83. Tsui KH, Lee WL, Seow KM, Yang LW, Wang SY, Wang PH, Chang CL, Yen MS, Cheng JT, Chen CP. (2014) Effect of gonadotropin-releasing hormone agonist on ES-2 ovarian cancer cells. Taiwan J Obstet Gynecol53 (1): 35-42. [PMID:24767644]

84. Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL, Flanagan CA, Dong K, Gillo B, Sealfon SC. (1992) Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol Endocrinol6: 1163-1169. [PMID:1324422]

85. Tsutsumi R, Mistry D, Webster NJ. (2010) Signaling responses to pulsatile gonadotropin-releasing hormone in LbetaT2 gonadotrope cells. J. Biol. Chem.285 (26): 20262-72. [PMID:20406815]

86. Van Poppel H. (2010) Evaluation of degarelix in the management of prostate cancer. Cancer Manag Res2: 39-52. [PMID:21188095]

87. Wang C, Ma Y, Feng S, Liu K, Zhou N. (2015) Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate: synthesis and in vitro evaluation. J. Pept. Sci.21 (7): 569-76. [PMID:25851250]

88. Wu HM, Wang HS, Huang HY, Lai CH, Lee CL, Soong YK, Leung PC. (2013) Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the invasiveness of endometrial cancer cells through the GnRH-I receptor and mitogen-activated protein kinase (MAPK)-dependent activation of matrix metalloproteinase (MMP)-2. BMC Cancer13: 300. [PMID:23786715]

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Adriaan P. IJzerman, Laura H. Heitman.
Gonadotrophin-releasing hormone receptors: GnRH1 receptor. Last modified on 24/02/2017. Accessed on 21/11/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=256.