Membrane rafts and GnRH receptor signaling

Abstract

The binding of hypothalamic gonadotropin-releasing hormone (GnRH) to the pituitary GnRH receptor (GnRHR) is essential for reproductive function by stimulating the synthesis and secretion of gonadotropic hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). Engagement of the GnRHR by GnRH initiates a complex series of signaling events that include the activation of various mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK). GnRHR signaling is thought to initiate within specialized microdomains in the plasma membrane termed membrane rafts. These microdomains are enriched in sphingolipid and cholesterol and are believed to be highly dynamic organizing centers for receptors and their cognate signaling molecules associated with the plasma membrane. Within this review we discuss the composition and role of membrane rafts in cell signaling and examine evidence that the mammalian type I GnRHR is constitutively and exclusively localized to these membrane microdomains in various experimental models. We conclude that membrane raft composition and organization potentially underlie the functional ability of GnRH to elicit the assembly of multi-protein signaling complexes necessary for downstream signaling to the ERK pathway that ultimately is critical for controlling fertility.

Identification of estradiol/ERα-regulated genes in the mouse pituitary

“…AEBP1, verified here as an estrogen/ERa-dependent gene in the proestrus pituitary (Fig. 2), and as previously shown in the white adipose tissue (Zhang et al 2005), maintains the activation of MAPK by protecting it from the effects of a MAPK-specific phosphatase (Kim et al 2001, Navratil et al 2010. The signal pathways activated by GnRH-R include major members of the MAPK family (Yang et al 2005, Dobkin-Bekman et al 2006.…”

“…Aebp1 has been shown to be estrogen/ERa-regulated in other tissues (Zhang et al 2005). The Aebp1-encoded protein is also an augmenter of MAPK function, which is significant considering that MAPK family downstream regulators are known to be activated by GnRH (Kim et al 2001, Navratil et al 2010. Opn3 was chosen because of its known role in exocytosis in other cell types (Henkel et al 2006).…”

Gonadotropin releasing hormone activation of the mTORC2/Rictor complex regulates actin remodeling and ERK activity in LβT2 cells

“…For example, proteomic analysis reveals that many of the molecular components regulating the actin cytoskeleton associate with membrane rafts (Chichili and Rodgers, 2007; Head, Patel and Insel, 2014). Interestingly, the GnRHR, Gα q/11 , calmodulin, Raf-1, MEKs, and ERKs themselves are localized within specialized membrane lipid raft microdomains (Bliss, Navratil, Breed et al, 2007; Navratil, Bliss, Berghorn et al, 2003; Navratil, Bliss and Roberson, 2010). In several cell types, mTORC2 is also localized to the plasma membrane and partitions into lipid rafts (Gao, Lowry, Zhou et al, 2011; Hill, Feng and Hemmings, 2002; Partovian, Ju, Zhuang et al, 2008).…”

Gonadotropin-releasing hormone signaling: An information theoretic approach

“…These include not only the conventional isoforms of PKC, but also the ubiquitous Ca 2+ sensor calmodulin (CaM), as well as calmodulin-dependent protein kinases (CaMK), the calmodulin dependent phosphatase calcineurin, and one of its major effectors, the Ca 2+ dependent transcription factor NFAT (nuclear factor of activated T-cells) (3,13,14). This brief overview omits *Manuscript Click here to view linked References many known components of the GnRH signaling network, which are reviewed in more detail elsewhere (1)(2)(3)(4)9,10,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). …”