A regulator of G Protein signaling, RGS3, inhibits gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion

A truncated version of RGS3 (RGS3T = RGS3 314–519) inhibited gonadotropin releasing hormone-stimulated inositol trisphosphate production more potently than did RSG3 in gonadotropin releasing hormone receptor-bearing COS cells. An RSG3/glutathione-S-transferase fusion protein bound more 35S-Gqα than any other member of the G protein family tested. Adenoviral-mediated RGS3 gene transfer in pituitary gonadotropes inhibited gonadotropin releasing hormone-stimulated luteinizing hormone secretion in a dose-related fashion. Adeno-RGS3 also inhibited gonadotropin releasing hormone stimulated 3H-inositol phosphate accumulation, consistent with a molecular site of action at the Gqα protein.RGS3 inhibits gonadotropin releasing hormone-stimulated second messenger production (inositol trisphosphate) as well as luteinizing hormone secretion from rat pituitary gonadotropes apparently by binding and suppressing the transduction properties of Gqα protein function. A version of RGS3 that is amino-terminally truncated is even more potent than intact RGS3 at inhibiting gonadotropin releasing hormone-stimulated inositol trisphosphate production.A near-universal feature of cell signaling via seven transmembrane, G protein-coupled receptors is attenuation of a cellular response upon prolonged exposure to an extracellular stimulus [1]. This desensitization process is well-established for GnRH-stimulated LH secretion from pituitary gonadotropes [2,3], and occurs after about 6 h of continued exposure to GnRH in rats [3]; removal of GnRH permits recovery from the profound suppression of LH secretion, albeit rather slowly (2–4 days; 4). The molecular mechanisms involved in GnRH-induced desensitization are poorly understood, but they do not appear to be due to alterations in GnRH receptor expression [5,6] or to changes in LH concentrations in the pituitary gland [7,8].Earlier, we presented evidence that a regulator of G protein signaling, RGS3, might participate in the regulation of GnRH recept