Disease relevance of Gnrhr

• We tested whether transgenic over expression of Insl3 can reverse inguinoscrotal cryptorchidism in mice deficient in Gnrhr or Hoxa10 genes [1].
• The pituitary tumors express the alpha-, FSHbeta-, and LHbeta-subunits and the GnRH-R messenger RNA, all markers of a gonadotrope but not of other anterior pituitary cell lineages [2].
• This synergistic interaction is specific to FSHbeta, because only additive effects of these two hormones are observed on LH beta-subunit, GnRH receptor, and mouse mammary tumor virus gene expression [3].
• Induction of apoptotic or lytic death in an ovarian adenocarcinoma cell line by antibodies generated against a synthetic N-terminal extracellular domain gonadotropin-releasing hormone receptor peptide [4].
• A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation [5].

High impact information on Gnrhr

• Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism [6].
• Essential role of the homeodomain for pituitary homeobox 1 activation of mouse gonadotropin-releasing hormone receptor gene expression through interactions with c-Jun and DNA [7].
• We have sought the expression of the GnRH peptide and functional GnRH receptor (GnRH-R) in human tissues and cell lines to investigate the possibility of an autocrine growth regulation mechanism [8].
• A small interfering RNA knockdown of type I GnRH receptor levels reduced PR activation by GnRHs, while progesterone-dependent PR activation was unaffected [9].
• In rat or mouse GnRHR that lacks Lys191, the bridge is non-essential and receptor is efficiently routed to the plasma membrane [10].

Biological context of Gnrhr

• The absence of a carboxyl-terminal cytoplasmic domain indicates the importance of other regions of the GnRH receptor in agonist-induced signal transduction, and possibly in receptor desensitization and sequestration [11].
• Analysis of the kinetics of recovery of ERK inducibility after cholesterol normalization supported the conclusion that reestablishment of the association of the GnRHR and ERKs with the membrane raft compartment was not sufficient for reconstitution of signaling activity [12].
• To understand these mechanisms in more depth, we generated transgenic mice bearing the 3.3-kb rat GnRH-R promoter linked to the human placental alkaline phosphatase reporter gene [13].
• Contained within this region are three elements important for expression in alphaT3-1 cells: a Steroidogenic Factor-1 binding site (SF-1), an Activator Protein-1(AP-1) element, and an element termed the GnRH receptor activating sequence or GRAS [14].
• Several potential protein kinase C phosphorylation sites which might mediate heterologous desensitization are present on the GnRH receptor [15].

Anatomical context of Gnrhr

• Rat WT retains the ability to oligomerize (since human and mouse mutants exert a DN effect on rat (r) WT sequence) but, unlike human or mouse, escapes the DN effect of GnRH receptor (Gn-RHR) mutants because rGnRHR mutants route to the plasma membrane with higher efficiency than mouse or human mutants [16].
• Steroid and pulsatile gonadotropin-releasing hormone (GnRH) regulation of luteinizing hormone and GnRH receptor in a novel gonadotrope cell line [17].
• The promoter of the rat gonadotropin-releasing hormone receptor gene directs the expression of the human placental alkaline phosphatase reporter gene in gonadotrope cells in the anterior pituitary gland as well as in multiple extrapituitary tissues [13].
• We have localized the GRHR gene to the q13.1-q21.1 region of the human chromosome 4 using mapping panels of human/rodent somatic cell hybrids containing different human chromosomes or different regions of human chromosome 4 [18].
• Immunolocalization of a gonadotropin-releasing hormone receptor site in murine endometrium that mediates apoptosis [19].

Associations of Gnrhr with chemical compounds

• Oct-1 and nuclear factor Y bind to the SURG-1 element to direct basal and gonadotropin-releasing hormone (GnRH)-stimulated mouse GnRH receptor gene transcription [20].
• When secretion was stimulated on day 4 with 54 mM [K+] pulses, bypassing the GnRH-R, the LH-secretory response indicated that the GnRH pulse history as well as estradiol and dexamethasone have actions on L beta T2-secretory capacity distinct from changes in the GnRH-R [17].
• An analysis of the role of this conserved residue (Leu(237)) in GnRH receptor function revealed that the binding affinities of the L237I and L237V mutant receptors were unchanged, but their abilities to mediate GnRH-induced inositol phosphate signaling, G protein coupling, and agonist-induced internalization were significantly impaired [21].
• Mediation of cyclic AMP signaling by the first intracellular loop of the gonadotropin-releasing hormone receptor [22].
• These findings indicate that cAMP signaling from the GnRH receptor is dependent on specific residues in the 1i loop that are not essential for activation of the phosphoinositide signaling pathway [22].

Physical interactions of Gnrhr

• It appears that luteal phase endometrium of mice expresses a GnRH receptor moiety that is coupled to a cell death (endonuclease) transduction pathway [19].
• The increased binding of 125I-[His5,D-Tyr6] GnRH has allowed the development of a sensitive GnRH receptor binding assay for analysis of mutant GnRH receptors that exhibit decreased ligand binding [23].
• The third intracellular loop of the rat gonadotropin-releasing hormone receptor couples the receptor to Gs- and G(q/11)-mediated signal transduction pathways: evidence from loop fragment transfection in GGH3 cells [24].

Regulatory relationships of Gnrhr

• Here we show that the rat GnRH-R promoter drives the expression of the reporter gene in pituitary cells expressing the LHbeta and/or FSHbeta subunit but not in TSHbeta- or GH-positive cells [13].
• These results suggest that AP-1 proteins and glucocorticoid receptor regulate transcription of the GnRH-R promoter in a heterologous system [25].
• Activation of phospholipase D by GnRH-A was dose- and time-dependent and was blocked by a GnRH receptor antagonist [D-pClPhe2,D-Trp3.6]GnRH [26].
• Pituitary adenylate cyclase-activating polypeptide and cyclic adenosine 3',5'-monophosphate stimulate the promoter activity of the rat gonadotropin-releasing hormone receptor gene via a bipartite response element in gonadotrope-derived cells [27].

Other interactions of Gnrhr

• MATERIALS AND METHODS: Hoxa10 and Gnrhr deficient mice were intercrossed with Insl3 transgenic mice [1].
• RESULTS: Transgenic over expression of Insl3 failed to restore normal testicular descent in Hoxa10 or Gnrhr deficient males [1].
• Overexpression of NF-YA increased GnRHR promoter activity, whereas expression of a dominant negative NF-YA mutant decreased activity, further supporting a role of NF-Y in regulation of mGnRHR gene transcription [20].
• Furthermore, using linkage analysis of single-strand conformational polymorphisms, the murine GRHR gene was localized to mouse chromosome 5, linked to the endogenous retroviral marker Pmv-11 [18].
• These findings indicate that the conserved apolar residue (Leu(237)) in the third intracellular loop is an important determinant of GnRH receptor expression and activation, and possibly that of other G protein-coupled receptors [21].

Analytical, diagnostic and therapeutic context of Gnrhr

• Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor [11].
• Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcription-PCR and Southern blotting of the PCR product [8].
• In this report, we used competitive reverse transcription PCR to quantitate the expression of GnRH and GnRH-R mRNA in lymphoid organs throughout the estrous cycle in mice [28].
• In order to define the production of GnRH as well as GnRH-R in the mammary gland at the molecular level we examined their gene expression in various functional stages of the mouse mammary gland using the reverse transcriptase-polymerase chain reaction (RT-PCR) [29].
• The attachment site of PAnt- to the receptor was localized between residues 11 and 19 of the extracellular N-terminal domain of the receptor by peptide mapping studies using natural sequence differences between human, mouse and sheep GnRH receptors, as well as a panel of GnRH receptor constructs with a series of engineered protease cleavage sites [30].

References