Mechanism of Gonadotrophin Releasing Hormone Receptor Mediated Regulation of G-Proteins in Clonal Pituitary Gonadotrophs
Guanine nucleotide binding proteins (G-proteins) function to transduce hormonal and sensory signals from plasma membrane receptors to effectors to regulate cellular functions. Binding of gonadotrophin releasing hormone (GnRH) receptor agonist to its receptor causes production of the second messengers inositiol-1,4,5-triphosphate (IP3) and sn-1,2-diacyglycerol (DAG) through the hydrolysis of phosphatidylinositol-4,5-bisphosphate because this receptor is coupled to Gq and G11 G-proteins. Prolonged exposure of αT3-1 pituitary gonadotrophs to a GnRH agonist results in marked downregulation of α-subunits of Gqα/11. The agonist-mediated downregulation is concentration and time-dependent and is not altered by treatment of cells with protein kinase C (PKC) activators and inhibitors. However the turnover of Gqα/G11α is substantially accelerated in the presence of agonist as revealed through 35S-labelled pulse chase experiments. By contrast the rate of degradation of the G-protein Gi2α is unaffected by agonist treatment. Analysis of Gqα/G11α mRNA levels by reverse transcription/polymerase chain reaction (RT/PCR) demonstrated no differences between control and agonist-treated cells. These studies indicate that GnRH receptor agonist-mediated down regulation of Gqα/G11α is independent of PKC and is a reflection of enhanced proteolysis of the activated G-proteins.
KeywordsGnRH Agonist Inositol Phosphate GnRH Analogue GnRH Receptor Guanine Nucleotide Binding Protein
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