KEGG   PATHWAY: hsa04912Help
Entry
hsa04912                    Pathway                                
Name
GnRH signaling pathway - Homo sapiens (human)
Description
Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.
Class
Organismal Systems; Endocrine system
BRITE hierarchy
Pathway map
GnRH signaling pathway
hsa04912

All organismsOrtholog table
Disease
H00255  
Hypogonadotropic hypogonadism
H00746  
Hypokalemic periodic paralysis (HypoPP)
H00937  
Precocious puberty
H01253  
Isolated follicle-stimulating hormone deficiency (IFSHD)
Drug
D00573  
Goserelin acetate (JAN)
D00988  
Gonadorelin hydrochloride (USP)
D00989  
Leuprorelin acetate (JAN)
D00990  
Nafarelin acetate (JAN/USAN)
D01685  
Cetrorelix acetate (JAN/USAN)
D01831  
Buserelin acetate (JAN/USAN)
D02116  
Histrelin acetate
D02369  
Histrelin (USAN/INN)
D02738  
Abarelix (USAN/INN)
D03061  
Batimastat (USAN/INN)
D03267  
Gonadorelin diacetate (JP16)
D03701  
Detirelix acetate (USAN)
D04302  
Ganirelix acetate (JAN/USAN)
D04361  
Gonadorelin acetate (USAN)
D04405  
Goserelin (USAN/INN)
D04644  
Iturelix (USAN/INN)
D04823  
Lutrelin acetate (USAN)
D05599  
Prazarelix acetate (USAN)
D06247  
Triptorelin (USAN/INN)
D06248  
Triptorelin pamoate (USAN)
D07259  
Buserelin (INN)
D07665  
Cetrorelix (INN)
D08010  
Ganirelix (INN)
D08027  
Gonadorelin (INN)
D08113  
Leuprorelin (INN)
D08241  
Nafarelin (INN)
D08635  
Degarelix acetate (USAN)
D08649  
Triptorelin acetate
D08901  
Degarelix (INN/USAN)
D09335  
Elagolix (USAN/INN)
D09336  
Elagolix sodium (USAN)
D09400  
Degarelix acetate (JAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
2796  
GNRH1; gonadotropin-releasing hormone 1 (luteinizing-releasing hormone) [KO:K05252]
2797  
GNRH2; gonadotropin-releasing hormone 2 [KO:K05252]
2798  
GNRHR; gonadotropin-releasing hormone receptor [KO:K04280]
2778  
GNAS; GNAS complex locus [KO:K04632]
107  
ADCY1; adenylate cyclase 1 (brain) [KO:K08041] [EC:4.6.1.1]
108  
ADCY2; adenylate cyclase 2 (brain) [KO:K08042] [EC:4.6.1.1]
109  
ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  
ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  
ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  
ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  
ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  
ADCY8; adenylate cyclase 8 (brain) [KO:K08048] [EC:4.6.1.1]
115  
ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
5566  
PRKACA; protein kinase, cAMP-dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
5567  
PRKACB; protein kinase, cAMP-dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
5568  
PRKACG; protein kinase, cAMP-dependent, catalytic, gamma [KO:K04345] [EC:2.7.11.11]
5613  
PRKX; protein kinase, X-linked [KO:K04345] [EC:2.7.11.11]
468  
ATF4; activating transcription factor 4 (tax-responsive enhancer element B67) [KO:K04374]
2776  
GNAQ; guanine nucleotide binding protein (G protein), q polypeptide [KO:K04634]
2767  
GNA11; guanine nucleotide binding protein (G protein), alpha 11 (Gq class) [KO:K04635]
23236  
PLCB1; phospholipase C, beta 1 (phosphoinositide-specific) [KO:K05858] [EC:3.1.4.11]
5330  
PLCB2; phospholipase C, beta 2 [KO:K05858] [EC:3.1.4.11]
5331  
PLCB3; phospholipase C, beta 3 (phosphatidylinositol-specific) [KO:K05858] [EC:3.1.4.11]
5332  
PLCB4; phospholipase C, beta 4 [KO:K05858] [EC:3.1.4.11]
3708  
ITPR1; inositol 1,4,5-trisphosphate receptor, type 1 [KO:K04958]
3709  
ITPR2; inositol 1,4,5-trisphosphate receptor, type 2 [KO:K04959]
3710  
ITPR3; inositol 1,4,5-trisphosphate receptor, type 3 [KO:K04960]
810  
CALML3; calmodulin-like 3 [KO:K02183]
805  
CALM2; calmodulin 2 (phosphorylase kinase, delta) [KO:K02183]
808  
CALM3; calmodulin 3 (phosphorylase kinase, delta) [KO:K02183]
801  
CALM1; calmodulin 1 (phosphorylase kinase, delta) [KO:K02183]
163688  
CALML6; calmodulin-like 6 [KO:K02183]
51806  
CALML5; calmodulin-like 5 [KO:K02183]
815  
CAMK2A; calcium/calmodulin-dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
817  
CAMK2D; calcium/calmodulin-dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
816  
CAMK2B; calcium/calmodulin-dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
818  
CAMK2G; calcium/calmodulin-dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
775  
CACNA1C; calcium channel, voltage-dependent, L type, alpha 1C subunit [KO:K04850]
776  
CACNA1D; calcium channel, voltage-dependent, L type, alpha 1D subunit [KO:K04851]
778  
CACNA1F; calcium channel, voltage-dependent, L type, alpha 1F subunit [KO:K04853]
779  
CACNA1S; calcium channel, voltage-dependent, L type, alpha 1S subunit [KO:K04857]
4214  
MAP3K1; mitogen-activated protein kinase kinase kinase 1, E3 ubiquitin protein ligase [KO:K04416] [EC:2.7.11.25]
10746  
MAP3K2; mitogen-activated protein kinase kinase kinase 2 [KO:K04420] [EC:2.7.11.25]
4215  
MAP3K3; mitogen-activated protein kinase kinase kinase 3 [KO:K04421] [EC:2.7.11.25]
4216  
MAP3K4; mitogen-activated protein kinase kinase kinase 4 [KO:K04428] [EC:2.7.11.25]
5606  
MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  
MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  
MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  
MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  
MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  
MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
5598  
MAPK7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
123745  
PLA2G4E; phospholipase A2, group IVE [KO:K16342] [EC:3.1.1.4]
5321  
PLA2G4A; phospholipase A2, group IVA (cytosolic, calcium-dependent) [KO:K16342] [EC:3.1.1.4]
8681  
JMJD7-PLA2G4B; JMJD7-PLA2G4B readthrough [KO:K16342] [EC:3.1.1.4]
PLA2G4B; phospholipase A2, group IVB (cytosolic) [KO:K16342] [EC:3.1.1.4]
8605  
PLA2G4C; phospholipase A2, group IVC (cytosolic, calcium-independent) [KO:K16342] [EC:3.1.1.4]
283748  
PLA2G4D; phospholipase A2, group IVD (cytosolic) [KO:K16342] [EC:3.1.1.4]
255189  
PLA2G4F; phospholipase A2, group IVF [KO:K16342] [EC:3.1.1.4]
5337  
PLD1; phospholipase D1, phosphatidylcholine-specific [KO:K01115] [EC:3.1.4.4]
5338  
PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
6714  
SRC; v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) [KO:K05704] [EC:2.7.10.2]
998  
CDC42; cell division cycle 42 [KO:K04393]
6416  
MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
5609  
MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
5599  
MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  
MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  
MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
3725  
JUN; jun proto-oncogene [KO:K04448]
3972  
LHB; luteinizing hormone beta polypeptide [KO:K08521]
1081  
CGA; glycoprotein hormones, alpha polypeptide [KO:K08522]
2488  
FSHB; follicle stimulating hormone, beta polypeptide [KO:K05250]
2185  
PTK2B; protein tyrosine kinase 2 beta [KO:K05871] [EC:2.7.10.2]
4313  
MMP2; matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase) [KO:K01398] [EC:3.4.24.24]
4323  
MMP14; matrix metallopeptidase 14 (membrane-inserted) [KO:K07763] [EC:3.4.24.80]
1839  
HBEGF; heparin-binding EGF-like growth factor [KO:K08523]
1956  
EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2885  
GRB2; growth factor receptor-bound protein 2 [KO:K04364]
6654  
SOS1; son of sevenless homolog 1 (Drosophila) [KO:K03099]
6655  
SOS2; son of sevenless homolog 2 (Drosophila) [KO:K03099]
3265  
HRAS; v-Ha-ras Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
5894  
RAF1; v-raf-1 murine leukemia viral oncogene homolog 1 [KO:K04366] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2002  
ELK1; ELK1, member of ETS oncogene family [KO:K04375]
5578  
PRKCA; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C, beta [KO:K02677] [EC:2.7.11.13]
5580  
PRKCD; protein kinase C, delta [KO:K06068] [EC:2.7.11.13]
Compound
C00076  
Calcium cation
C00165  
Diacylglycerol
C00219  
Arachidonate
C00416  
Phosphatidate
C00575  
3',5'-Cyclic AMP
C01245  
D-myo-Inositol 1,4,5-trisphosphate
Reference
  Authors
Ruf F, Sealfon SC.
  Title
Genomics view of gonadotrope signaling circuits.
  Journal
Trends Endocrinol Metab 15:331-8 (2004)
Reference
  Authors
Harrison GS, Wierman ME, Nett TM, Glode LM.
  Title
Gonadotropin-releasing hormone and its receptor in normal and malignant cells.
  Journal
Endocr Relat Cancer 11:725-48 (2004)
Reference
  Authors
Pawson AJ, McNeilly AS.
  Title
The pituitary effects of GnRH.
  Journal
Anim Reprod Sci 88:75-94 (2005)
Reference
  Authors
DeGroot LJ, Jameson JL (ed).
  Title
Endocrinology (Fifth edition)
  Journal
Elsevier Saunders (2006)
Reference
  Authors
Naor Z, Benard O, Seger R.
  Title
Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor.
  Journal
Trends Endocrinol Metab 11:91-9 (2000)
Reference
  Authors
Ruf F, Fink MY, Sealfon SC.
  Title
Structure of the GnRH receptor-stimulated signaling network: insights from genomics.
  Journal
Front Neuroendocrinol 24:181-99 (2003)
Reference
  Authors
Farshori PQ, Shah BH, Arora KK, Martinez-Fuentes A, Catt KJ.
  Title
Activation and nuclear translocation of PKCdelta, Pyk2 and ERK1/2 by gonadotropin releasing hormone in HEK293 cells.
  Journal
J Steroid Biochem Mol Biol 85:337-47 (2003)
Reference
  Authors
Shah BH, Catt KJ.
  Title
Matrix metalloproteinases in reproductive endocrinology.
  Journal
Trends Endocrinol Metab 15:47-9 (2004)
Reference
  Authors
Roelle S, Grosse R, Aigner A, Krell HW, Czubayko F, Gudermann T.
  Title
Matrix metalloproteinases 2 and 9 mediate epidermal growth factor receptor transactivation by gonadotropin-releasing hormone.
  Journal
J Biol Chem 278:47307-18 (2003)
KO pathway
 
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