Role of phospholipase-D and phosphatidic acid in mediating gonadotropin-releasing hormone-induced inhibition of preantral granulosa cell differentiation.
The activation of phospholipase-D (PLD) was previously implicated in mediating the differentiative action of GnRH on preovulatory granulosa cells. The activation of PLD and the action of its product, phosphatidic acid (PA), were further studied in preantral granulosa cells, where GnRH exerts an antidifferentiative effect. A GnRH receptor agonist (GnRH-A) activated PLD in the cells, causing a sustained elevation of phosphatidylethanol and a transient increase in cellular PA levels. PLD was also activated by 12-O-tetradecanoylphorbol-13-acetate (TPA). Both GnRH-A and TPA inhibited FSH-induced production of progesterone, a marker of granulosa cell differentiation. D,L-Propranolol, which elevates cellular PA by inhibiting its degradation, mimicked the antidifferentiative action of GnRH-A and TPA in a dose-dependent manner. Addition of PA similarly inhibited FSH-induced progesterone production in a dose-dependent manner. The effect of forskolin, which mimics the steroidogenic effect of FSH by elevating intracellular levels of cAMP, could also be suppressed by GnRH-A and PA. FSH- and cAMP-induced differentiation of preantral granulosa cells is characterized by cell rounding and breakdown of actin filament bundles. This effect is inhibited by GnRH-A and TPA as well as PA. It is concluded that activation of PLD and the resultant production of PA could mediate the antidifferentiative action of GnRH in preantral granulosa cells. Moreover, GnRH-induced PLD-generated signals counteract the FSH-induced cAMP-dependent signals that modulate the organization of the actin cytoskeleton characteristic of steroidogenic cells.
Amsterdam
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Department of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
Dantes
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Liscovitch
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D000199:Actins / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects*; D010712:Phosphatidic Acids / Q000502:physiology*; D010739:Phospholipase D / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D010712:Phosphatidic Acids; D007987:Gonadotropin-Releasing Hormone; D010739:Phospholipase D