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Questions And Answer

• Structure

  GHRH(1–29) is the bioactive core of human GHRH. The N-terminal tyrosine residue with selected aromatic rings is important for the high bioactivity in human and nonrodent mammalian GHRH. The amino acid sequence of GHRH shows higher identities between the human, porcine, bovine, and caprine species, but the rat and mouse are exceptions. The sequence of the C-terminus is highly variable among species while the N-terminus is more conserved. The N-terminal region (1–27) of GHRH is well conserved in nonmammalian vertebrates. Zebrafish GHRH (1–27) shows 74.1%, 81.5%, and 81.5% similarity to the Xenopus tropicalis, chicken, and human counterparts, respectively. Mr 12,447 (GHRH(1-44), Mr 5,039), pI 10.3 (GHRH(1- 44), pI 11.5). Soluble in acidic aqueous solution (e.g., 1% acetic acid). Lyophilized GHRH is stable at room temperature for 2months, and recommended storage is below -18°C with desiccation.;

• Gene, mRNA, and precursor

  The human GHRH gene, GHRH, location 20q11.2, consists of five exons. GHRH mRNA has 459 bases that encode a signal peptide of 24 aa residues, a mature protein of 44 aa residues, and a C-peptide of 31 aa residues with unknown function. In nonmammalian vertebrates, the GHRH-like peptide and PACAP were first believed to be encoded by the same gene, but later actual GHRH and PACAP were found to be encoded by two distinct genes.;

• Synthesis and release

  The human GHRH gene, GHRH, location 20q11.2, consists of five exons. GHRH mRNA has 459 bases that encode a signal peptide of 24 aa residues, a mature protein of 44 aa residues, and a C-peptide of 31 aa residues with unknown function. In nonmammalian vertebrates, the GHRH-like peptide and PACAP were first believed to be encoded by the same gene, but later actual GHRH and PACAP were found to be encoded by two distinct genes.;

• Synthesis and release

  The synthesis and release of GHRH are regulated by sex hormones, aging, the negative feedback effect of GH, and diverse pathological conditions. Gsh-1 has been considered a transcriptional factor of Ghrh expression in the rat hypothalamus. GHRH synthesis is inhibited by somatostatin (SS). The expression levels of the SS receptor, sst2A, in GHRH neurons are higher in female mice than male mice. The production of hypothalamic GHRH is decreased by aging. It is also negatively regulated by the feedback of GH, whereas ghrelin stimulates GHRH release.;

• Receptors

  GHRH-R belongs to the GPCR B II subclass, highly selective for GHRH. The GHRH-R of most mammals consists of 423 aa residues. The N-terminal extracellular domain contains a site for N-glycosylation as well as six cysteine residues and an aspartate residue that are conserved in this receptor family. The third intracellular loop and the C-terminal intracellular domain contain several potential phosphorylation sites, which may regulate signaling and receptor internalization. It is mainly expressed in the pituitary.;

• Agonists and Antagonists

  Tesamorelin, sermorelin (GHRH(1–29)-NH2), and CJC-1295 are agonists. Antagonists comprise the antibodies or peptides to GHRH-R: JV-1-10, JV-1-36, JV-1-37, JV-1-38, JV-1-39, JV-1-40, JV-1-41, JV-1-42, JV-1-43, JV-1-62, JV-1-63, MZ-4-71, MZ-4-169, MZ-4-181, MZ-4-243, MZ-5-78, MZ-5-156, MZ-5-192, MZ-6-55, [Ac-Tyr1, D-Arg2] GHRH(1–29)-NH2.;

• Biological functions

  GHRH receptor mRNA is expressed in several organs, especially in the adrenal, digestive tract, and kidney. The primary function of GHRH is to stimulate GH synthesis and release from the anterior pituitary somatotrophs. GHRH activates cell proliferation, cell differentiation, and growth of somatotrophs, and is also involved in the modulation of appetite and feeding behavior, the regulation of sleeping, the control of jejunal motility, and the increase in leptin levels in modest obesity .;

• Clinical implications

  Mutations in the GHRH gene have never been described. A single base change in the GHRH-R gene in human somatotropinoma confers hypersensitivity to GHRH binding. Pit-1 mutation inducing the low gene expression of GHRH-R can lead to the development of dwarfism.;

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