Regulation of the gonadotropin-releasing hormone receptor (GnRHR) by RGS proteins: role of the GnRHR carboxyl-terminus.

The cytoplasmic carboxyl-terminus of G-protein coupled receptors (GPCRs), absent in the mammalian gonadotropin-releasing hormone receptor (GnRHR), plays an important role in receptor expression, desensitization, internalization and efficiency of coupling to G proteins. Regulators of G protein signaling (RGS) likewise are involved in regulating GPCR-G protein mediated responses and can regulate transcription of other genes. In this study, we evaluate differential expression, ligand binding and effector coupling of the rat GnRHR (rGnRHR) and a chimera of rGnRHR with the pre-mammalian carboxyl domain (rGnRHR-C-tail). Membrane expression of the chimeric receptor and G(q)alpha and G(s)alpha-mediated signaling was increased 2- and 1.5-fold, respectively by RGS10, while RGS3 did not interfere with rGnRHR and rGnRHR-C-tail cell surface expression in spite of negatively regulating GnRH-stimulated G(q)alpha-mediated signaling by both receptors. The rGnRHR and rGnRHR-C-tail showed similar internalization rates in the presence of either RGS protein, indicating that the modification of rGnRHR expression and regulation in the presence of a carboxyl-terminus by RGS10 was not caused by alteration of the internalization rate. The observations in this study implicate the carboxyl domain of the receptor as a site of interaction for RGS10, but not RGS3. This is the first evidence of an altered cell surface expression and regulation of the GnRHR bearing a carboxyl-terminus by RGS proteins.

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