Growth hormone-releasing hormone and other stimulators of growth hormone secretion
The pulsatile nature of growth hormone (GH) secretion results from the complex interplay between the hypothalamus and anterior pituitary (Tannenbaum, 1991; Robinson, 1997; Smith et al., 1997) (Figure 20.1). The potent and specific stimulatory factor of GH release, growth hormone-releasing hormone (GHRH, GRF) (Bertherat, Bluet-Pajot & Epelbaum, 1995), is a 44 amino acid C-amidated peptide that was isolated by four separate groups in 1982 from human pancreatic tumours (Thorner, 1993). It is a member of the vasoactive intestinal polypeptide (VIP) family (Watson & Arkinstall, 1994) and primarily produced in the arcuate and ventromedial nuclei neurons (Sawchenko & Swanson, 1990; Martin & Millard, 1986). Beside the hypothalamus, GHRH is expressed in the duodenum, gastric antrum, placenta, testes, sensory ganglion cells and pancreas. Following binding to its G-protein coupled receptor (GPC-R) (Mayo, 1992), GHRH was shown to elevate GH levels specifically via an adenylate cyclase cAMP-dependent pathway (Frohman, Downs & Chomczynski, 1992). Furthermore, an elevation in intracellular Ca2+ through L-type Ca2+ channels as well as an inward protein kinase A sensitive Na+ channel were shown to be induced by GHRH (Kato & Sukuma, 1997). Functional analysis of GHRH analogs determined that the N-terminus (amino acids 1–29) of the GHRH peptide contained the minimum structure for full agonist activity (Felix, Heimer & Mowles, 1985). Acetylated and des-amino derivatives were proven to be more potent compounds than GHRH presumably through proteolysis resistance (Coy et al., 1985; Frohman et al., 1989). Optimization of GHRH's α-helical and amphiphilic character via a Gly→Ala15 change, lead to a fourfold increase in GH-releasing activity (Felix et al., 1988).