Growth hormone secretagogues (GHSs) release growth hormone (GH) via both the hypothalamus and the pituitary gland, and also stimulate ACTH and prolactin release. The presence of a seven transmembrane, G protein-coupled specific receptor has been described both in the hypothalamus and the pituitary of several species, including the human. Recently, the presence of the GH-secretagogue receptor (GHS-R) mRNA has also been described in human adenomatous and fetal pituitary tissue as well as in ectopic endocrine tumours, and it has been shown to be functionally active in a GHRH- and ACTH-secreting carcinoid. Nevertheless, the effects of GHSs and their non-peptide analogues on in vitro cultured human pituitary somatotrophs and on rat hypothalamic incubations were investigated well before the specific GHS-R had been identified. It has been shown that GHSs stimulate in vitro growth hormone (GH) release from somatotroph cells. As shown with rat pituitary cells, GHRP-6 induces protein kinase C (PKC)-dependent GH secretion and a biphasic increase in intracellular Ca by tumorous human somatotrophs in culture.
The Ca response involves a rapid but transient increase followed by an attenuated response and then a longer lasting PKCdependent plateau phase. Additionally, direct involvement of the adenyl cyclase-coupled GHRH-receptor in the actions of GHRP-2 and GHRP-6 was excluded. Because of these findings, it was suspected that GHRP-6 could induce hydrolysis of membrane phosphatidyl inositol (PI), since this transduction system yields diacylglycerol (DAG) and inositol trisphosphate (IP3); this in turn leads to activation of PKC, mobilisation of intracellular Ca stores and opening of ion channels. This assertion was confirmed by an in vitro cell culture study in which GHRP-6 and its methylated derivative, hexarelin, were shown to powerfully stimulate PI hydrolysis in human pituitary somatotrophinomas removed from patients with acromegaly. The effects were dose-dependent, maximal stimulation being observed with 100 nmol/1 after two hours of exposure, and GH secretion increased in parallel. The non-peptide GHRP analogue, L-692,429, exerted identical effects on PI hydrolysis and GH secretion. It thus appears that the primary mechanism of action of GHSs on human pituitary cells is via activation of the PI-PKC/Ca transduction system. The stimulatory effects of GHSs on GH secretion can be reduced or aboUshed by phloretin, an inhibitor of PKC, and also by W7, which inhibits the intracellular Ca-binding messenger, calmodulin. In contrast, inhibition of protein kinase A with Rp-adenosine-3,5-cyclic monophosphothioate (Rp-cAMPS) and blockade of the GHRH receptor with specific antagonists both failed to significantly alter the effects of GHRP-2 and GHRP-6 and hexarelin, whereas they were able to inhibit the stimulatory effects GHRH.
The recent identification and characterisation of the specific receptor to which GHSs bind further supports the hypothesis that GHSs act via the PI-PKC/Ca transduction system, since it was shown to be coupled to G, a G protein capable of inducing phospholipase C activity and hence PI hydrolysis. The GHS receptor is probably over-expressed in somatotroph adenomas. The stimulatory effects of GHSs on both PI hydrolysis and GH secretion by tumorous human pituitary somatotrophs is far more consistent than those exerted by GHRH. In our most comprehensive series, only 4 (9,3%) of 43 GH-secreting tumours failed to respond to GHRP-6 in culture, while about 35% showed a failure to respond to GHRH. This finding is similar to that observed when using activators of PKC. Additionally, expression of gsp oncogenes, which leads to constitutive adenyl cyclase activity and elevated cAMP production, does not appear to influence the effects of GHSs on PI hydrolysis and GH secretion, emphasising their independent mechanism of action. Nevertheless, GHSs are still able to influence cAMP production under some circumstances. Both GHRP-2 and GHRP-6 are able to potentiate the stimulatory effects of GHRH on cAMP production by tumorous human somatotrophs in culture, similar to findings with normal rat pituitary cells. Moreover, GHRP-2 and GHRP-6 can slightly but significantly stimulate basal cAMP production in those tumours expressing g5p oncogenes. Such results suggest that there may be intracellular cross-talk between the PI and adenyl cyclase transduction pathways, as shown to occur in other cell types. This might be achieved by PKC-induced phosphorylation of the catalytic subunit of adenyl cyclase and the inhibitory protein, Gj.
The effects of synthetic GH-secretagogues on human prolactin secretion have also been studied. The non-peptide GHRP analogue, L-692,429, powerfully stimulated prolactin secretion by a mixed somatotrophic-lactotrophic human pituitary tumour in culture, confirming the in vivo effects observed in acromegalic patients. Additionally, some, but not all, pure prolactin-secreting tumours expressed the GHS-R mRNA and also responded to GHSs, both in terms of prolactin secretion and PI hydrolysis. In contrast, in patients with prolactinoma no further rise was observed in circulating prolactin levels after GHS stimulation. Such findings indicate that tumorous human lactotrophs may also possess the GHS-R, but further studies are required to fully elucidate the role of GHSs in normal prolactin secretion. Nevertheless, it is worth noting that prolactin secretion is also influenced by both the PKA and PKC transduction pathways and thus parallels can be drawn with the control of GH secretion.
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