Gonadotropin releasing hormone signaling
Gonadotropin-releasing hormone (GnRH) is the first key
hormone of reproduction in vertebrates. GnRH is released
from the hypothalamus in a pulsatile manner and stimulates pituitary gonadotropes to
synthesize and release Luteinizing hormone beta (LH-beta)
and Follicle stimulating hormone, beta polypeptide
(FSH-beta). The gonadotropins
(LH-beta and FSH-beta)
stimulate sex hormone production and gametogenesis. GnRH
regulates the hypothalamo-pituitary axis , .
The binding of GnRH to Gonadotropin-releasing hormone
receptor (GnRHR) is a critical factor for receptor
activation, initiation and propagation of intracellular signaling.
GnRHR is a G-protein coupled receptor.
GnRHR interacts with multiple G-proteins such as
G-protein alpha-q/11 and G-protein alpha-s
, , .
G-protein alpha-q/11 activated by the
GnRHR stimulates Ca2+-independent of Phospholipase C beta
(PLC beta). PLC beta cleaves
Phosphatidylinositol 4,5-bisphosphate (Ptdins(4,5)P2) to
generate Inositol-1,4,5-trisphosphate (IP3) and
Diacylglycerol (DAG) , .
DAG and IP3 stimulate Protein
kinase C, type delta (PKC-delta) and epsilon
(PKC-epsilon) and mobilize intracellular Ca2+,
respectively , , .
GnRH stimulates rapid Ca2+
mobilization from internal IP3-sensitive stores, followed by
external Ca2+ influx via nifedipine-sensitive L-type
voltage-sensitive Ca2+ channels (L-type Ca(II) channel, alpha 1C
subunit) , .
The PKC-delta and
PKC-epsilon are then able to bind to and activate V-raf-1
murine leukemia viral oncogene homolog 1 (c-Raf-1)/
Mitogen-activated protein kinase kinase 1 and 2 (MEK1
Mitogen activated protein kinases 3 and 1 (Erk (MAPK1/3))
cascade , . In addition, Erk
(MAPK1/3) activation is partially dependent on Proto-oncogene
tyrosine-protein kinase (c-Src)/ v-Ha-ras Harvey rat
sarcoma viral oncogene homolog (H-Ras) cascade in
Dynamin-dependent manner , . Erk (MAPK1/3) also activated by PTK2B protein
tyrosine kinase 2 beta (Pyk2(FAK2))/ c-Src
/ Growth factor receptor bound protein 2
(Grb2)/ Son of sevenless homolog
c-Raf-1 pathway. Pyk2(FAK2) probably
activated by c-Src . Erk
(MAPK1/3) activated by GnRH subsequently
phosphorylates ELK1 member of ETS oncogene family (Elk-1).
Elk-1 regulates expression of Early growth response 1
(EGR1)  and FBJ osteosarcoma oncogene
GnRH stimulates expression of Dual specificity
phosphatase 1 and 2 (MKP-1 and
activates MKP-2 most likely through Erk
EGR1 pathway. MKP-1 and
MKP-2 serve as negative feedback regulators that modulate
Erk (MAPK1/3) and JNK activity
GnRH stimulates Mitogen-activated protein kinases
(JNK(MAPK8-10)) activity by a pathway that includes
sequential activation of PKC-epsilon /
c-Src/ Cell division cycle 42
(CDC42)/ Mitogen-activated protein kinase kinase kinase 1
(MEKK1) . Activated
JNK phosphorylates jun oncogene (c-Jun),
thereby regulate expression of Secretogranin II , LH-beta , Activating
transcription factor 3 (ATF-3) and Glycoprotein hormone
alpha-subunit gene promoter (CG alpha) . In
addition, ATF-3 stimulates expression of CG
alpha , Secretogranin II
 and inhibits expression of
Secretogranin 1 .
Furthermore, MEKK1 can activate Mitogen-activated protein
kinase p38 (most likely p38alpha
(MAPK14)) . p38 and
Erk (MAPK1/3) can regulate Adenylate cyclase activating
polypeptide 1 (PACAP), FSH-beta
and GnRHR transcription via activation of
Activator protein-1 (AP-1) factors , , . p38 phosphorylates
EGR1 . Erk
(MAPK1/3) and Protein kinase A
(PKA) also activate
EGR1 through activation cAMP responsive element binding
protein (CREB1) and Elk-1
. EGR1 regulates
expression of PER1 ,
ATF-3, Secretogranin 1  and LH-beta 
GnRH also activates Activating transcription factor 2
(ATF-2) probably through p38
and Erk (MAPK1/3), thus regulating
expression of ATF-3 .
Activation of G-protein alpha-s further activates the
Adenylate cyclase / Cyclic adenosine monophosphate
(cAMP)/ PKA/ CREB1 . In addition, Ca2+ (via intermediate, presumably -
Ca2+/calmodulin-dependent protein kinase II (CaMK II)
activates CREB1. CREB1 also
activated by PKC / MEK1/2/
ERK1/2/ Ribosomal protein S6 kinase
(p90RSK) cascade . CREB1
regulates expression of
Secretogranin II , , Nuclear receptor subfamily 4 group A member 1
LH-beta, FSH-beta , Follistatin , ATF-3 ,
PACAP  and EGR1
. Nur77 activated by
cAMP/ PKA regulates expression of
FSH-beta , .
Moreover, Ca2+/calmodulin-dependent protein kinase I (CaMK
I) activates Myocyte enhancer factor 2D
(MEF2D) by phosphorylation of Histone deacetylase 5 and 4
(HDAC5 and HDAC4).
MEF2D regulates expression of
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