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Potential Role for a Regulator of G Protein Signaling (RGS3) in Gonadotropin-Releasing Hormone (GnRH) Stimulated Desensitization

Department of Physiology and Biophysics (J.D.N., L.W.D., J.C.S., L.C.M.), Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294; and Laboratory of Immunoregulation (A.S., K.M.D., J.H.K.), National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

The cellular and molecular mechanisms of gonadotrope desensitization are unknown but transduction of the GnRH signal is known to involve sequentially the GnRH receptor, Gq protein, phospholipase C ß-1, inositol-1,4,5-trisphosphate (IP₃), and intracellular Ca⁺² release. Here, we report the results of studies of a new family of proteins known as regulators of G protein signaling (RGS) that recently have been implicated in desensitization of several ligand induced processes. Using DNA-mediated transfection, we co-expressed the GnRH receptor and RGS1, 2, 3, or 4 in COS-1 cells. Control cells and those expressing RGS1, 2, and 4 produced five fold increases in IP₃ levels during the 30 sec after treatment with GnRH. In contrast, RGS3 expression suppressed by 75% the GnRH-induced IP₃ responses. RGS3 was shown to bind Gq protein in a model in vitro system: recombinant RGS3-glutathione-S-transferase (GST) fusion protein bound five-fold more ³⁵S-met labeled Gq protein than did with GST alone, suggesting that the mechanism of RGS3 action is attenuation of Gq protein activation of phospholipase C. RGS3 mRNA and protein were observed to be expressed endogenously in the gonadotropic T3-1 cell line. These results suggest a potential role for RGS3 in modulating the LH secretory responsiveness of the pituitary gonadotrope to GnRH.

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