Gonadotropin Signaling in the Ovary Chapter 20 Gonadotropin Signaling in the Ovary © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20. 1 The gonadotropins and gonadotropin receptors FIGURE 20.1 The gonadotropins and gonadotropin receptors. (A) A schematic of the family of dimeric glycoproteins hormones, which includes the pituitary gonadotropins FSH and LH, pituitary thyroid-stimulating hormone, and, in some species, placental chorionic gonadotropin. The α subunit is shared by all four hormones. (B) Generic schematic of the glycoprotein hormone receptors, indicating the large extracellular domain and the seven membrane-spanning domains characteristic of GPCRs. A significant portion of the extracellular domain is composed of leucine-rich repeats, each composed of a β-strand followed by an α-helix, and these are proposed to form a horseshoe-shaped domain as shown that likely plays an important role in ligand binding. (C) A model showing the view that the extracellular domain of the receptor plays a repressive role in the absence of ligand binding and that ligand interaction and ensuing conformational changes relieve this repression, allowing G protein activation. Source: Modeled after Ref. 52. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20. 2 FSH signals via cAMP to activate PKA FIGURE 20.2 FSH signals via cAMP to activate PKA. Two PKA substrates in immature granulosa cells are CREB and histone H3. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.3 Schematic model of the association of AKAPs with PKA, other protein kinases (PKs), PDEs, substrates, and anchoring sites in cells. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.4 FSH via cAMP/PKA activates ERK by stimulating the phosphorylation and consequent dissociation of an inhibitory protein tyrosine phosphatase (PTP). A tonic pathway that includes Ca2+, SRC, EGF receptor, RAS, and RAF promotes MEK phosphorylation. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20. 5 Summary of identified ERK and p38 MAPK substrates FIGURE 20.5 Summary of identified ERK and p38 MAPK substrates. Arrows indicate stimulation; perpendicular lines indicate inhibition of activity. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.6 FSH via cAMP/PKA signals to activate PI-3K, leading to mTOR1-stimulated translation and inhibition of FOXO1 and FOXO3 targets. FSH and activin synergize to promote gene expression. Multiple arrows indicate more than one step in pathway. Potential contribution of IGF-1 and IGF-1 receptor is indicated by dashed lines. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.7 Mechanism by which FSH via PKA activates PI-3K leading to AKT activation. Multiple arrows indicate more than one step in the pathway. Potential contribution of IGF-1 and IGF-1 receptor is indicated by dashed lines. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20. 8 Summary of identified AKT substrates FIGURE 20.8 Summary of identified AKT substrates. Arrows indicate stimulation; perpendicular lines indicate inhibition. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.9 Schematic diagram of the rescue of hypophosphorylated β-catenin from proteosomal degradation by WNT signaling. A potential route for FSH to inhibit phosphorylation of β-catenin via AKT is depicted. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.10 Schematic diagram of the mitochondrialdependent apoptotic pathway in ovarian cells and sites at which FSH has been reported to inhibit (perpendicular lines) or stimulate (arrows). Bold names represent proteins identified in granulosa cells. Dashed lines represent expected but not demonstrated regulation. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.11 Schematic diagram of the pathway leading to NF-κB-dependent activation of target genes. Potential sites of FSH stimulation of this pathway are indicated. Dashed lines represent expected but not demonstrated regulation. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20. 12 Composite regulation of FSHresponsive gene targets FIGURE 20.12 Composite regulation of FSHresponsive gene targets. Question marks (?) for ERK signaling reflect inhibition by a MEK inhibitor but not proof of target phosphorylation. Regulation of Lhcgr by Egr-1 is suggested by literature. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.13 LH signals that regulate ovulation, cumulus granulosa cell expansion, and luteinization. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 20.14 Mechanism by which LH promotes oocyte maturation. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition