The original growth hormone-releasing peptide (GHRP), which was synthesised by Bowers and named GHRP-6, stimulates GH secretion in a relatively specific manner although it is only a weak GH secretagogue. Many more potent GHRPs have now been developed including hexarehn, GHRP-1 and GHRP-2. The most recent development in this field has been the identification of a GHRP receptor in several animal species including man. In spite of the efficacy and relative specificity of GHRPs for the stimulation of GH release, and the existence of a specific receptor for GHRPs, no endogenous ligand has yet been identified for these synthetic peptides. There is good evidence, however, that such a ligand exists since activity can be found in the hypophysial portal blood of sheep using a bioassay that utilises cells transfected with the cloned receptor.
This activity is closely correlated with the secretion of GH. Since it is only a matter of time before the endogenous GHRP(s) is/are identified and purified, it is timely to revise our understanding of the way that GH synthesis and secretion is regulated. Our present understanding of these processes relies on the integrated actions of the stimulatory factor, growth hormone releasing factor (GRF) and the inhibitory factor, somatostatin (SRIF). The current model, which largely depends upon data from the male rat, is one which dictates that GH release is solely determined by the sum of the combined effects of GRF and SRIF. This is supported by experimental data of reciprocal alterations in the hypophysial portal blood levels of GRF and SRIF in the rat, suggesting that these patterns relate to the pulsatile secretion of GH in an explicit manner. On the other hand, studies in sheep have not found such a close relationship between GRF, SRIF and GH in the sheep, calling into question the general applicability of the male rat model. The possible existence of an endogenous GHRP would further complicate the issue. The signal transduction systems mediating tlie responses to GHRPs in pituitary somatotrophs have been studied in some detail.
This article discusses these whilst clearly recognising that there are likely to be actions of GHRPs at other levels (hypothalamus) and in other pituitary cell types. The GHRP receptors that were recently identified in the human, swine, and rat pituitary have a high degree of similarity. These receptors clearly belong to a family which is different to that of the GRF receptor and can be blocked only by specific antagonists. A series of non-peptidergic compounds (such as MK 0677) have a very high affinity for this receptor. Contrary to the data obtained in human, swine and rat somatotrophs, we have found that GRF receptor antagonist prevents GHRP-2 stimulated GH release in sheep pituitary cells in vitro. This suggests some relationship between the GHRP-2 binding sites and the GRF receptor, at least in this species. It has been reported that GHRP-6 interacts with a novel low-affinity GHRH binding site in the rat anterior pituitaiy and Sethumadhavan identified two classes of GHRP-binding sites using it as a ligand. It seems possible, therefore, that an unidentified receptor exists that has a low affinity for GRF and a high affinity for GHRP-2. Another possibility that we considered was that GHRP might bind to a site on the GRF receptor different to that employed by GRF. This was tested using a GC cell line with overexpression of the GRF receptor. In these cells, cAMP levels were increased by GRF but not GHRP-2 or GHRP-6, and the effect of GRF was blocked by a GRF receptor antagonist. This strongly suggests that the GHRPs do not act via GRF receptors. It remains possible, however, that there is more than one type of GHRP receptor, one (GHRP-Rl) that is blocked by the GRF antagonist and one (GHRP-R2) that is not.
One could speculate that GHRP-Rl has a similar binding affinity for GHRP-6, GHRP-1 and GHRP-2 whereas GHRP-R2 would have a higher affinity for GHRP-2 than for GHRP-6 or GHRP-1. GHRP-R2 may also have a low affinity for GRF-binding which would explain the effects of blockade with it. Recently, a 57kD GHRP receptor was found in human, bovine and porcine pituitary glands using Hexarelin as binding ligand and this appears to differ from the 41kD receptor identified by Howard. The binding affinities of the two receptors are quite different with the 57 kD type having a high affinity to Hexarelin and low affinity to MK 0677. This provides realistic evidence that there is more that one type of GHRP receptor. The GHRP receptors couple to G proteins based on evidence of activation of adenylyl cyclase by GHRP-2, activation of PKC, release of intracellular Ca and increased phosphatidylinositol (PI) turnover following treatment with GHRP-6, non-peptidergic secretagogues and GHRP-2. Because both adenylyl cyclase and phospholipase C are activated by GHRP, Gs and Gq are most likely to be involved in these responses.
The CHRP receptor identified by Howard is coupled to Gq which is known to mediate the activation of phospholipase C (PLC). In accordance with this, co-expression of the CHRP receptor and Gqll protein increased the Ca response to CHRP in Xenopiis oocytes. It has also been reported that GHRPs and non-peptidergic GH secretagogues increase PI turnover via an activation of PLC in human acromegalic tumour cells. Whether PLC is activated in ovine or rat somatotrophs by any GHRP is still an open question. Investigation of this issue would be useful given the difference in response of sheep cells to GHRP-2 and other versions of GHRP.
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