GHRH Signaling
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GHRH Signaling

GHRH (Growth Hormone-Releasing Hormone) is a hypothalamic hormone that is essential for normal expansion of the somatotrope lineage during pituitary development. GHRH is produced by GHRH cells in the hypothalamus and reaches the adenohypophysis via the portal system. It stimulates the release of GH (Growth Hormone)/Somatotropin from the adenohypophysis. GH is required for normal postnatal growth, having a critical role in bone growth as well as important regulatory effects on protein, carbohydrate, and lipid metabolism (Ref.1 & 2).

GHRH first appears in the human hypothalamus between 18 and 29 weeks of gestation, which corresponds to the appearance of fetal pituitary somatrotropes. It is a 44-amino acid peptide, synthesized by neurons in the hypothalamic arcuate nucleus and released into hypothalamic Cpituitary portal vessels in the median eminence. Axons of these GHRH neurons project to the median eminence and terminate on the capillaries of the pituitary portal system to stimulate GH release (Ref.3). GHRH stimulates GH secretion from somatotroph cells of the anterior pituitary via a pathway that involves GHRHR (GHRH Receptor).  Both GHRH and the GHRHR are expressed during the late stages of embryonic life and are essential for the expansion of the somatotrope lineage. The GHRHR is a member of the secretin family of seven-transmembrane, GPCRs (G-Protein-Coupled Receptor) and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is 44┬ĘC45 kD. It was first cloned from the anterior pituitary gland, where it is most abundantly expressed. GHRHR is coupled, through G-proteins, to multiple signal transduction pathways (Ref.4).

Binding of GHRH to its receptor activates the Alpha-subunit (G-AlphaS) of the closely associated G-Protein complex, thus stimulating membrane-bound AC (Adenylyl Cyclase) and increasing intracellular cAMP (cyclic Adenosine Monophosphate) concentrations (Ref.5). cAMP binds to and activates the regulatory subunits of PKA (Protein Kinase-A), which in turn release catalytic subunits that translocate to the nucleus and phosphorylate the transcription factor CREB (cAMP Response Element Binding protein). Phosphorylated CREB, together with its coactivators, p300 and CBP (CREB Binding Protein) enhances the transcription of various genes by binding to specific DNA elements within gene promoter regions, referred to as CREs (cAMP-Response Elements). The genes activated by GHRH and cAMP contain CREs in their promoter regions (Ref.2). CREB, via direct and indirect mechanisms, stimulates GH production via transcription of the GH gene as well as increasing transcription of the GHRHR gene as part of a short positive feedback loop (Ref.3).

In addition, GHRH-mediated cAMP-dependent and cAMP-independent pathways cause an influx of extracellular Ca2+, leading to the release of GH secretory vesicles and resulting in a rapid increase in circulating GH concentrations (Ref.6). Thus, the AC/cAMP/Ca2+ signaling system plays an important role in the stimulatory action of GHRH on the growth of various cell lines (Ref.4). Activation of GHRHRs by GHRH results in the activation of PIP2, through the activation of G-AlphaI. PIP2 activation in turn, leads to the opening of a Na+ Channel (Sodium Channel) in the somatotrope, leading to its depolarization. The resultant change in the intracellular voltage in turn opens a voltage-gated Ca2+ Channel (Calcium Channel), allowing the influx of Calcium, which directly causes the release of premade GH, stored in secretory granules (Ref.2). GHRH also acutely stimulates PLC (Phospholipase-C) through the G-Beta-Gamma complexes of heterotrimeric G-proteins. PLC activation produces both PIP2 and IP3 (Inositol Triphosphate) which leads to release of intracellular Ca2+ from the ER (Endoplasmic Reticulum) (Ref.4). Thus, multiple signaling mechanisms activated by GHRH could be used to mediate the proliferative effects of the hormone (Ref.1). Beyond its distribution in the CNS (Central Nervous System), GHRH mRNA expression has been demonstrated in peripheral cells and tissues as well, for example, in the pancreas, the epithelial mucosa of the gastrointestinal tract and the tumour cells.

GHRH is essential for expansion of the somatotrope lineage during pituitary development, but excessive GHRH secretion and/or action results in unregulated somatotrope proliferation leading to hyperplasia and neoplastic transformation (Ref.2). Likewise, a decrease in GHRH production or actions is associated with somatotrope hypoplasia.  If the hypothalamus does not make enough GHRH, or if the pituitary gland does not have GH to release, GHD (Growth Hormone Deficiency) can occur. GH released by GHRH, stimulates liver IGF1 gene transcription and could directly stimulate tumor IGF1 production. GH-induced increase in IGF1 can activate type-I IGF1 receptors located on tumor cells, thereby mediating the transcription of genes important for cell proliferation and have been linked with malignant transformation, tumor progression, and metastasis of various cancers (Ref.6). It is of importance that the endogenous production of GHRH was detected in human SCLC (Small-Cell Lung Carcinoma), sarcoma cell lines, and the prostate, ovarian and the endometrial cancers (Ref.7). Thus, antagonistic analogs of GHRH could be useful for the treatment of endocrine disorders such as acromegaly, diabetic retinopathy, or diabetic nephropathy, but their main applications are likely to be in cancer therapy (Ref.8).