Signal transduction mechanisms of Ca2+ mobilizing hormones: the case of gonadotropin-releasing hormone.

Multiple (at least seven) steps are involved in GnRH-induced gonadotropin secretion and gonadotropin gene expression. After binding to specific receptors located exclusively on pituitary gonadotrophs, GnRH stimulates a rapid phosphodiesteric hydrolysis of phosphoinositides for which no rise in [Ca2+]i is required. Activation of PLC is most likely mediated by a pertussis toxin-insensitive GTP-binding protein (Gp). In its activated state (Gp-GTP) the binding affinity of GnRH to is receptor is reduced. Rapid formation of IP3 will enhance Ca2+ release from intracellular sources most likely via a specific IP3 receptor. The transient Ca2+ rise might be responsible for a burst phase of LH release lasting for about 100 sec, which is not dependent on extracellular Ca2+. The backbone moiety of the phosphoinositides, DG, and the elevated [Ca2+]i are most likely responsible for translocation of PKC subspecies from the cytosol to the membrane. The most likely candidates are alpha- and beta II-PKC. The activated PKC subspecies phosphorylate substrate proteins which activate secretory reactions and participate in gonadotropin gene expression. In parallel Ca2(+)-influx via nifedipine-sensitive and insensitive channels further elevates [Ca2+]i, which participates in the sustained phase of gonadotropin secretion in concert with the activated PKCs. GnRH also triggers the release of AA and the formation of lipoxygenase and/or epoxygenase products of the fatty acid which are also involved in the process of the exocytosis. We predict that the continuous supply of DG and AA needed for GnRH action is also provided via activated PLD which will also supply phosphatidic acid, the role of which is as yet unclear. The interaction of the various second messengers involved in GnRH action (IP3, Ca2+, DG, AA) and their relative roles in gonadotropin secretion and gonadotropin gene expression await further investigation. In several aspects GnRH action on gonadotropin secretion is unique when compared to other Ca2(+)-mobilizing ligands: 1) At physiological concentrations GnRH up-regulates its own receptors whereas most ligands down-regulate the respective receptor; 2) PKC up-regulates GnRH receptors whereas in most cases PKC down-regulates the ligand receptor; 3) GnRH stimulation of PLC activity is most likely mediated by Gp whereas some Ca2(+)-mobilizing ligands operate via Gi; 4) Activated PKC does not exert negative feedback upon GnRH-induced inositol phosphate production as is the case with several other peptides; 5) Activated PKC might be responsible for Ca2+ influx whereas in several other systems PKC is inhibitory to Ca2+ influx.(ABSTRACT TRUNCATED AT 400 WORDS)