To date, only one receptor for the GH secretagogues has been identified that is present at both pituitary and hypothalamic sites (8). With the large number of peptide and nonpeptide GH secretagogues now available for study, it is emerging that these compounds have subtle differences in action, raising the possibility that multiple GH secre-tagogue receptors or receptor subtypes may exist.
The electrical activation of arcuate neurons by GHRP-6 has a number of distinctive characteristics; most particularly the activation is extremely long lasting. Typical excitation is sustained for over 1 h following a bolus administration at a just-suprathreshold dose, and typically excitation reaches its peak intensity only after a latency of 5-10 min; this response appears to be even later for nonpeptide agonists than for GHRP-6, although the degree of electrical activation of responsive cells appears similar. It is unclear whether this reflects slower penetration of the blood-brain barrier by the nonpeptide secreta-gogues or a different mode of action. Moreover, the nonpeptide secretagogues MK-0677 (unpublished observation) and L-692,585 (7) appear to be slightly, but consistently, less effective than GHRP-6 for inducing Fos protein expression in the arcuate nucleus. It may be that these nonpeptide GH secretagogues are more selective than GHRP-6 in their central action or that they are simply less potent. Certainly, comparing the potencies of these secretagogues at the pituitary level for stimulating GH secretion, there is no reason to suppose that the nonpeptide GH secretagogues are less potent than GHRP-6 (34). Moreover, the magnitude of electrical activation of responsive cells in the arcuate nucleus appears very similar whether the activation is induced by GHRP-6 or by a nonpeptide GH secretagogue. Thus, it is possible that GHRP-6 is more effective than the nonpeptide secretagogues in inducing Fos protein expression by binding to more than one receptor or receptor subtype in the hypothalamus.
Other evidence in support of the existence of multiple GH secretagogue receptors is suggested from studies in dwarf lit/lit mice, a GH-deficient mutant resulting from a point mutation in the extracellular binding domain of the GHRH receptor (35). The pituitaries of these mice appear to be unresponsive not only to GHRH (36), but also to GHRP-6 (37), suggesting that the GH secretagogue receptor may be dependent on the presence of a functionally intact GHRH receptor. Although this may be true at the pituitary level, the authors demonstrated that the hypothalamic response to GHRP-6 (in this case, the induc tion of Fos protein) remains intact (38). Taken together, these observations seem to suggest that the presence of functional GHRP-6 receptors in the pituitary depends on the existence of a functional GHRH receptor, whereas the presence of functional GHRP-6 receptors in the hypothalamus is independent of the presence of functional GHRH receptors.
The effects of Hexarelin pretreatment (3-10 d) on subsequent GH responses to GH secretagogues are very different in neonatal vs young adult rats: Hexarelin enhanced GH secretion in neonates and inhibited GH secretion in young adult rats (39). One possible explanation of this finding is that in the early postnatal period a different subtype of GH secretagogue receptor is expressed in the pituitary or that both the neonatal and adult subtype are expressed together.
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