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Species sequence differences determine the interaction of GnRH receptor with the cellular quality control system.

ABSTRACT: Plasma membrane expression (PME) of the human GnRHR (hGnRHR) is regulated by a primate-specific Lys(191) which destabilizes a Cys(14)-Cys(200) bridge required by the cellular quality control system (QCS). A 4-amino, non-contiguous "motif" (Leu(112), Gln(208), Leu(300), Asp(302)) is required for this effect. The hGnRHR sequence, with or without Lys(191), decreases PME and inositol phosphate (IP) production when co-expressed with calnexin, a QCS chaperone. WT rat GnRHR, decreases PME and IP production, when co-expressed with calnexin, but to a lesser degree than hGnRH. When the human sequence contains the rat motif, IP production is closer to that of rat GnRHR. When Lys(191) is deleted from hGnRHR and co-expressed with calnexin, IP production is similar to the rat sequence. When rat GnRHR containing Lys(191) and the human motif is co-expressed with calnexin, IP production is similar to cells expressing the hGnRHR. The motif sequence appears to be a determinant of calnexin recognition.

SUBMITTER: Cabrera-Wrooman A

PROVIDER: S-EPMC3795929 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Species sequence differences determine the interaction of GnRH receptor with the cellular quality control system.

Cabrera-Wrooman Alejandro A Janovick Jo Ann JA Conn P Michael PM

Molecular and cellular endocrinology 20130724 1-2

Plasma membrane expression (PME) of the human GnRHR (hGnRHR) is regulated by a primate-specific Lys(191) which destabilizes a Cys(14)-Cys(200) bridge required by the cellular quality control system (QCS). A 4-amino, non-contiguous "motif" (Leu(112), Gln(208), Leu(300), Asp(302)) is required for this effect. The hGnRHR sequence, with or without Lys(191), decreases PME and inositol phosphate (IP) production when co-expressed with calnexin, a QCS chaperone. WT rat GnRHR, decreases PME and IP produc ...[more]

PMID: 23891857

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Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the KallmannM-bM-^@M-^Ys syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization. In one experiment we compare the olfactrory sensory epithelium from wild-type embryos, at three times of development, i.e. E11.5, E12.5 and E14.5. In a second experiment we compare the olfactory sensory epithelium from wild-type embryo with that from Dlx5 knock-out embryos, at the age E12.5

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Species sequence differences determine the interaction of GnRH receptor with the cellular quality control system.

Publications

Species sequence differences determine the interaction of GnRH receptor with the cellular quality control system.

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