Reproduction - GnRH signaling

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 [1], [2].

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 [3], [4], [5].

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) [6], [7]. DAG and IP3 stimulate Protein kinase C, type delta (PKC-delta) and epsilon (PKC-epsilon) and mobilize intracellular Ca2+, respectively [6], [8], [9]. 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) [2], [10].

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 and MEK1)/ Mitogen activated protein kinases 3 and 1 (Erk (MAPK1/3)) cascade [11], [12]. 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 [12], [13]. 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 (SOS)/ H-Ras/ c-Raf-1 pathway. Pyk2(FAK2) probably activated by c-Src [14]. 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) [15] and FBJ osteosarcoma oncogene (c-Fos) [16].

GnRH stimulates expression of Dual specificity phosphatase 1 and 2 (MKP-1 and MKP-2). GnRH activates MKP-2 most likely through Erk (MAPK1/3)/ Elk-1/ EGR1 pathway. MKP-1 and MKP-2 serve as negative feedback regulators that modulate Erk (MAPK1/3) and JNK activity [17].

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) [18]. Activated JNK phosphorylates jun oncogene (c-Jun), thereby regulate expression of Secretogranin II [19], LH-beta [20], Activating transcription factor 3 (ATF-3) and Glycoprotein hormone alpha-subunit gene promoter (CG alpha) [21]. In addition, ATF-3 stimulates expression of CG alpha [21], Secretogranin II [19] and inhibits expression of Secretogranin 1 [22].

Furthermore, MEKK1 can activate Mitogen-activated protein kinase p38 (most likely p38alpha (MAPK14)) [23]. 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 [24], [25], [26]. p38 phosphorylates EGR1 [14]. Erk (MAPK1/3) and Protein kinase A (PKA) also activate EGR1 through activation cAMP responsive element binding protein (CREB1) and Elk-1 [15]. EGR1 regulates expression of PER1 [27], ATF-3, Secretogranin 1 [22] and LH-beta [28]

GnRH also activates Activating transcription factor 2 (ATF-2) probably through p38 and Erk (MAPK1/3), thus regulating expression of ATF-3 [22].

Activation of G-protein alpha-s further activates the Adenylate cyclase / Cyclic adenosine monophosphate (cAMP)/ PKA/ CREB1 [29]. 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 [30]. CREB1 regulates expression of Secretogranin II [19], [29], Nuclear receptor subfamily 4 group A member 1 (Nur77) [31], LH-beta, FSH-beta [32], Follistatin [33], ATF-3 [22], PACAP [26] and EGR1 [15]. Nur77 activated by cAMP/ PKA regulates expression of FSH-beta [31], [34].

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 FSH-beta [34].

References:

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