It is well established that GRF activates the cAMP/PKA pathway in somatotrophs and that this is fundamental to the release of GH. Part of the effect of SRIF is through inhibition of cAMP formation. In contrast, GHRP-6 and GHRP-1 have no direct effect on intracellular cAMP levels in rat and ovine somatotrophs. Nevertheless, GHRP-6 may synergise with GRF to increase intracellular cAMP levels. Similar results are also found for the non-peptidergic analogue L-692,429, but synergy could not be demonstrated with GHRP-1 and GRF.
This discrepancy suggests that the cAMP/PKA pathway is not the primary signalling route for GHRP-6 and GHRP-1. GHRP-2 increases intracellular cAMP levels in ovine (but not rat) somatotrophs. There is a dose-dependent increase in cAMP levels in response to GHRP-2 stimulation with corresponding effects on GH secretion. GHRP-2 stimulated GH secretion was blocked in these cells by an inhibitor of adenylyl cyclase and a cAMP binding antagonist. Thus, in sheep cells at least, GHRP-2 activates adenylyl cyclase leading to an increase in cAMP levels and activation of cAMP-dependent protein kinase A (PKA). Thus, PKA could phosphorylate transmembrane Ca channels to modify their properties in the manner observed by electrophysiological means. A significant species difference appears to exist between sheep and rat somatotrophs in terms of GH release in response to GHRP-2. Neither GHRP-6 nor GHRP-1 increases adenylyl cyclase activity in ovine pituitary cells. We propose therefore, that in ovine somatotrophs, the pathway employed by GHRP-2, resulting in an increase in cAMP levels, is different to that employed by either GHRP-6 or GHRP-1 in both rat and ovine pituitary cells. The mechanism by which GIIRP-2 activates adenylyl cyclase is not clear.
Although some subtypes of adenylyl cyclase can be activated by Ca, these do not appear to mediate the response to GHRP-2 since blockade of Ca influx does not affect the cAMP response. Although it is clear that GRF elevates cAMP levels in ovine somatotrophs, it may act through a cyclase which is different to that used by GHRP-2, since GHRP-2 and GRF have additive effects on both cAMP accumulation and GH secretion when both secretagogues are applied at maximal doses. In summaiy, GHRP-2 stimulates cAMP accumulation in ovine somatotrophs via activation of adenylyl cyclase, but this response is not seen in rat somatotrophs. This appears to be the pathway responsible for the stimulation of GH secretion by GHRP-2 in the sheep. GHRP-6 and GHRP-1 elevate cAMP levels in ovine, rat and human somatotrophs and ampUfy the cAMP response to GRF in rat pituitary cells. This suggests activation of different cyclases by the different secretagogues. As discussed, both the cAMP/PKA and the PLC/PKC systems appear to be involved in the GHRP-2 stimulation of GH release in ovine somatotrophs. GHRP-2 stimulates adenylyl cyclase activity, resulting in cAMP production, and also activates PKA which, in turn, leads to an increase in intracellular Ca and GH secretion.
Activation of the PKC pathway by GHRP-2 may positively potentiate the cAMP-PKA pathway by stimulating adenylyl cyclase activity and this potentiation of adenylyl cyclase activity may further increase the accumulation of Ca. A selective inhibitor for PKA (H89) had no effect on PMA- or GHRP-induced PKC translocation, but inhibited GH secretion in response to either PMA or GHRP-2, suggesting that the effect on GH release is dependent upon the cAMP-PKA pathway. It is therefore suggested that the stimulation of PKC translocation by GHRP-2 is not the major signalling system employed. PKC inhibitors only partially reduce GH secretion in response to GHRP-2, which also suggests that the PKC pathway is not mandatory for the action of GHRP-2 to induce GH secretion in ovine somatotrophs. Thus, we propose that the activation of PKC potentiates the action of GHRP-2.
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