GH secretion is directly related to the Ca and influx of Ca tluough voltagedependent Ca channels is increased by GRF and reduced by SRIF. There is no clear evidence, however, that either GRF or SRIF mobilises Ca from intracellular Ca storage sites. On the other hand, GHRP-6 causes the release of intracellular Ca as well as Ca influx through the cell membrane. In isolated rat somatotrophs, GHRP-6 evoked dual-phase increases in Ca; an initial transient increase due to intracellular Ca release and a second longer lasting phase due to the influx of Ca. In ovine pituitary cells, GHRP caused a subtle and transient increase in Ca even when extracellular Ca was chelated to zero. This probably involves the generation of inositol trisphosphate but this has not yet been demonstrated. In spite of the mobilisation of Ca from intracellular stores, the major contribution to the elevation of Ca is caused by influx of extracellular Ca.
It appears that this is an integral factor in the release of GH in response to GHRP because blockade of membrane Ca channels abolishes the secretory response. In somatotrophs, the major membrane Ca channels are of the voltage-gated T- and L-types. Studies of rat and sheep cells have respectively shown that GHRP-6 and GHRP-2 depolarize the cell membrane leading to the opening of these channels. Since this depolarization can only be recorded with the nystatin-perforated patch clamp configuration (which does not disturb intracellular systems), this impHes that an intact second messenger signalling systems are required for ion channel function. GHRP-2 increases voltage-gated T- and L- type Ca current. The measurement of Ca was performed on somatotroph-enriched cell populations and it is clear that GHRP-2, but not GnRH or TRH, increases CaJi levels in these cells. All of these effects of GHRP on the electrophysiological properties of the somatotroph cell membrane resemble those of GRF but are opposite to the effects of SRIF. The ion channels that are involved in depolarization of somatotroph cell membrane are not defined but it appears that Na channels do not play a major role in the response to CHRP. It is thought that voltage-gated Ca channel activation is partly responsible for the depolarization caused by GHRP-2, but K channels may also be involved; these have not been characterised in detail. In summary, the available data suggest that GHRP first causes the release of intracellular Ca and then causes Ca influx by an increase in membrane Ca permeability of the cell. The latter is due to membrane depolarization most likely via action of second messengers on Ca channel protein. It has been suggested that the action of GHRP-6 and the non-peptidergic analogue L692,429 to stimulate GH release from rat pituitary cells is mediated by protein kinase C (PKC).
The synergistic action of GHRP-6 and GRF on cAMP accumulation and GH secretion in rat pituitary cells may also be mediated by PKC. It should be noted however, that the specificity of the inhibitor (phloretin) has not been widely tested and the effect of this agent on other kinase systems is not defined. In particular, over the same dose range (10-200 iM), phloretin increased the opening probability of Ca-activated K channels which can hyperpolarize the cell membrane and prevent the stimulation of GH secretion by GHRP-6. Down-regulation of PKC with long-term treatment by phorbol, 12-myristate, 13-acetate (PMA, 1 jiM) partially blocked the effect of GHRP-6 on GH secretion, suggesting some involvement of PKC in the response. It was shown by Akman however, that GHRP-l still causes GH release following maximal stimulation of cells with PMA. In ovine pituitary cells GHRP-6 does not cause PKC translocation. Furthermore, down-regulation of PKC with PMA does not block GH release in response to GHRP-6 in sheep cells whereas PMA-stimulated GH release is totally abolished by the same treatment.
In contrast, GHRP-2 stimulates PKC translocation from cytosol to membrane in ovine somatotrophs in primary culture. The stimulation of PKC translocation by GHRP-2 is dose-dependent, with a maximal response reached at 10M. PKC inhibitors (Calphostin C, Chelerythrine, Staurosporine) and down-regulation of PKC by phorbol,12,13-dibutyrate (PDBu) causes only partial attenuation of this response. It seems likely therefore, that PKC is at least partially involved in the action of GHRP-2 (but not GHRP-6) in sheep cells. It is interesting to note that GRF also causes PKC translocation in ovine somatotrophs. It is possible to account for the response of ovine somatotrophs to GRF and GHRP-2 by activation of the cAMP/PKA pathway, but the concomitant activation of PKC may play a role to enhance the action of GHRP-2 on cAMP/PKA pathway.
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