Growth Hormone Releasing Hormone Receptor Family Related Drug Discovery Products

The 40- and 44- amino-acid peptides from pancreatic tumors that caused acromegaly in the absence of a pituitary tumor were identified and described as the growth hormone releasing factor. Hypothalamic growth hormone-releasing hormone (GHRH), which was later discovered, was eventually shown to be identical to the GHRH that had been recovered from the tumors. GHRH is a member of the superfamily of hormones that includes PACAP and glucagon, which is produced by the pituitary gland. Structure, distribution, function, and receptors connect these peptides.The 44 amino acid peptide's structure was determined to be as follows:

Fig.1. The structure of GHRH. (Siejka, 2012)

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Overview of Growth Hormone Releasing Hormone Receptor Family

As a result of the interaction between GHRHR and its ligand, adenylate cyclase is activated, which raises cAMP levels and, in turn, Ca²⁺ ion levels, leading to the release of GH into the bloodstream. The protein kinase A pathway is activated by the rise in cAMP, regulating cell proliferation and the production of GH and GHRHR. Although the inositol phosphate-diacylglycerol-protein kinase C system, the Ca²⁺ calmodulin system, and the arachidonic acid-eicosanoid system are thought to play a minor role, the adenylate cyclase-protein kinase A pathway is the main transduction pathway that mediates GHRH actions on somatotropic cells. Attenuated GH release results from continuous or repeated activation of GHRHR in the pituitary. The primary mechanism underlying the reduction of the GH response is receptor desensitization, which is characterized by the decoupling of the G protein that activates adenylate cyclase. This method, which is typical of this receptor class, is a two-step procedure that begins with the phosphorylation of the receptor by a G protein–coupled receptor kinase (GRK). The receptor is marked for beta-arrestin binding by the phosphorylation, which results in receptor silence.

Fig.2. Schematic cascade of GHRHR and its ligand. (Martari & Salvatori, 2009)

Growth Hormone Releasing Hormone Receptor Family Drug Discovery

The GHRHR is essential for the growth and proliferation of somatotroph cells as well as GH production and plays a critical role in the hypothalamus-pituitary axis. Although the TM region of the receptor protein appears to be more important for ligand selectivity, both the extracellular and TM domains are involved in ligand binding. Biallelic GHRHR mutant carriers have proportionate dwarfism, severe growth retardation, and very low levels of GH and IGF-1 in the serum. They respond well to GH therapy if it is started early in life, have an aberrant lipid profile, and have a buildup of belly fat.

References

1. Siejka, A.; et al.Antineoplastic action of growth hormone-releasing hormone (GHRH) antagonists. Recent Patents on Anti-Cancer Drug Discovery. 2012, 7(1): 56-63.
2. Martari, M.; Salvatori, R. Diseases associated with growth hormone‐releasing hormone receptor (GHRHR) mutations. Progress in molecular biology and translational science. 2009, 88: 57-84.