Luteinizing hormone receptor signaling regulates cofilin activity that is necessary for preovulatory granulosa cell steroidogenesis

Activation of the luteinizing hormone receptor (LHR) on preovulatory granulosa cells (PO GCs) stimulates the cAMP/Protein Kinase A (PKA) pathway to regulate expression of genes required for ovulation and luteinization. LHR signaling also initiates rearrangement of the actin cytoskeleton. As disruption of the actin cytoskeleton has been causally linked to steroidogenesis in various cell models, we sought to identify the cellular mechanisms that may modulate reorganization of the actin cytoskeleton and to determine whether cytoskeletal reorganization is required for steroidogenesis. Herein we report that LHR signaling in PO GCs promotes rapid dephosphosphorylation of the actin depolymerizing factor cofilin at Ser3 that is dependent on PKA. The LHR-stimulated dephosphorylation of cofilin(Ser3) switches on cofilin activity to bind and depolymerize actin filaments. Basal phosphorylation of cofilin(Ser3) is mediated by the active/GTP-bound small G protein Rho; LHR signaling promotes a decrease in active/GTP-bound Rho by a PKA-dependent mechanism. LHR-dependent Rho inactivation and subsequent activation of cofilin does not involve the ERK, epidermal growth factor receptor, or phosphatidylinositol-3 kinase pathways downstream of PKA. To understand the biological significance of cofilin activation, PO GCs were transduced with a mutant cofilin adenoviral vector in which Ser3 was mutated to Glu (S-E cofilin). Inactive S-E cofilin abolished LHR-mediated reorganization of the actin cytoskeleton and caused a 70% decrease in LHR-stimulated progesterone that is obligatory for ovulation. Taken together, these results show that LHR signaling via PKA activates cofilin-regulated rearrangement of the actin cytoskeleton that is required for progesterone secretion by PO GCs.