Signal transduction mechanism of the seabream growth hormone secretagogue receptor

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Abstract
We have recently cloned the full‐length cDNAs of the two growth hormone secretagogue receptor (GHSR) subtypes from a teleost species, the black seabream (Acanthopagrus schlegeli) [Mol. Cell. Endocrinol. 214 (2004) 81], namely sbGHSR‐1a and sbGHSR‐1b. Functional expression of these two receptor constructs in human embryonic kidney 293 (HEK293) cells indicated that stimulation of sbGHSR‐1a by growth hormone secretagogues (GHS) could evoke increases in intracellular Ca2+ concentration ([Ca2+]i), whereas sbGHSR‐1b appeared to play an inhibitory role on the signal transduction activity of sbGHSR‐1a. In the present study, we have further investigated the signal transduction mechanism of sbGHSR‐1a. The peptide GHS GHRP‐6 and the non‐peptide GHS L163,540 were able to trigger a receptor specific and phospholipase C (PLC)‐dependent elevation of [Ca2+]i in HEK293 cells stably expressing sbGHSR‐1a. This GHS‐induced calcium mobilization was also dependent on protein kinase C activated L‐type calcium channel opening. It was found that sbGHSR‐1a could function in an agonist‐independent manner as it exhibited a high basal activity of inositol phosphate production in the absence of GHS, indicating that the fish receptor is constitutively active. In addition, the extracellular signal‐regulated kinases 1 and 2 (ERK1/2) were found to be activated upon stimulation of sbGHSR‐1a by GHRP‐6. This observation provides direct evidence in the coupling of sbGHSR‐1a to ERK1/2 activation. Neither Gs nor Gi proteins are coupled to the receptor, as GHS did not induce cAMP production nor inhibit forskolin‐stimulated cAMP accumulation in the sbGHSR‐1a bearing cells. Furthermore, the ability of the GHSR antagonist d ‐Lys(3)‐GHRP‐6 to inhibit basal PLC and basal ERK1/2 activity suggests that this compound is an inverse agonist. In summary, the sbGHSR‐1a appears to couple through the Gq/11‐mediated pathway to activate PLC, resulting in increased IP3 production and Ca2+ mobilization from both intracellular and extracellular stores. Moreover, sbGHSR‐1a may trigger multiple signal transduction cascades to exert its physiological functions.

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