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The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH.

ABSTRACT: Gonadotropin secretion, which is elicited by GnRH stimulation of the anterior pituitary gonadotropes, is a critical feature of reproductive control and the maintenance of fertility. In addition, activation of the GnRH receptor (GnRHR) regulates transcription and translation of multiple factors that regulate the signaling response and synthesis of gonadotropins. GnRH stimulation results in a broad redistribution of mRNA between active and inactive polyribosomes within the cell, but the mechanism of redistribution is not known. The RNA-binding protein embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) binds to AU-rich elements in mRNA and is one of the most abundant mRNA-binding proteins in eukaryotic cells. It is known to serve as a core component of RNA-binding complexes that direct the fate of mRNA. In L?T2 gonadotropes, we showed that ELAVL1 binds to multiple mRNAs encoding factors that are crucial for gonadotropin synthesis and release. Association with some mRNAs is GnRH sensitive but does not correlate with abundance of binding. We also showed MAPK-dependent changes in intracellular localization of ELAVL1 in response to GnRH stimulation. Knockdown of ELAVL1 gene expression resulted in reduced Lhb and Gnrhr mRNA levels, reduced cell surface expression of GnRHR, and reduced LH secretion in response to GnRH stimulation. Overall, these observations not only support the role of ELAVL1 in GnRHR-mediated regulation of gene expression and LH secretion but also indicate that other factors may contribute to the precise fate of mRNA in response to GnRH stimulation of gonadotropes.

SUBMITTER: Terasaka T

PROVIDER: S-EPMC6660905 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH.

Terasaka Tomohiro T Kim Taeshin T Dave Hiral H Gangapurkar Bhakti B Nicholas Dequina A DA Muñoz Oscar O Terasaka Eri E Li Danmei D Lawson Mark A MA

Endocrinology 20190801 8

Gonadotropin secretion, which is elicited by GnRH stimulation of the anterior pituitary gonadotropes, is a critical feature of reproductive control and the maintenance of fertility. In addition, activation of the GnRH receptor (GnRHR) regulates transcription and translation of multiple factors that regulate the signaling response and synthesis of gonadotropins. GnRH stimulation results in a broad redistribution of mRNA between active and inactive polyribosomes within the cell, but the mechanism ...[more]

PMID: 31188427

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Project description:Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning ?-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins. Forty non-covalent interactions that bridge topologically equivalent residues in different transmembrane (TM) helices are conserved in class A GPCR structures, regardless of activation state. Conformation-independent interhelical contacts account for a conserved receptor protein structure and their importance in the GnRH receptor structure is supported by decreased expression of receptors with mutations of residues in the network. Many of the GnRH receptor mutations associated with congenital hypogonadotropic hypogonadism, including the Glu2.53(90) Lys mutation, involve amino acids that constitute the conserved network. Half of the ~250 intramolecular interactions in GPCRs differ between inactive and active structures. Conformation-specific interhelical contacts depend on amino acids changing partners during activation. Conserved inactive conformation-specific contacts prevent receptor activation by stabilizing proximity of TM helices 3 and 6 and a closed G protein-binding site. Mutations of GnRH receptor residues involved in these interactions, such as Arg3.50(139) of the DRY/S motif or Tyr7.53(323) of the N/DPxxY motif, increase or decrease receptor expression and efficiency of receptor coupling to G protein signaling, consistent with the native residues stabilizing the inactive GnRH receptor structure. Active conformation-specific interhelical contacts stabilize an open G protein-binding site. Progress in defining the GnRH-binding site has recently slowed, with evidence that Tyr6.58(290) contacts Tyr5 of GnRH, whereas other residues affect recognition of Trp3 and Gly10NH2. The surprisingly consistent observations that GnRH receptor mutations that disrupt GnRH binding have less effect on "conformationally constrained" GnRH peptides may now be explained by crystal structures of agonist-bound peptide receptors. Analysis of GPCR structures provides insight into GnRH receptor function.

Dataset Information

The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH.

Publications

The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH.

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