RAPID DESENSITIZATION OF GNRH-STIMULATED INTRACELLULAR SIGNALING EVENTS IN ALPHA-T3-1 AND HEK-293 CELLS EXPRESSING THE GNRH RECEPTOR

The gonadotropin-releasing hormone receptor (GnRH-R) desensitizes foll owing chronic exposure to GnRH or its agonists. However, it is not cer tain whether the GnRH-R undergoes rapid homologous desensitization ana logous Co other members of the G-protein coupled receptor (GPCR) super family. This study investigated rapid desensitization events in two ce ll lines expressing the GnRH-R; (the pituitary gonadotrope alpha T3-1 cell line and the stably transfected human embryonal kidney cells, HEK -293). In both cell types, total inositol phosphate (IP) production di d not desensitize, increasing linearly over 10 min. Short-term GnRH pr etreatment also did not desensitize the rapid phase (less than or equa l to 10sec) of the early Ins1,4,5P(3) response despite a partial desen sitization of the plateau phase (>1 min). It is likely that Ins1,4,5P( 3) metabolism rather than desensitization is responsible for this part ial effect. In contrast, GnRH-stimulated calcium responses did desensi tize in a dose-dependent fashion in both alpha T3-1 and HEK 293 cells expressing the GnRH-R. These results suggest that rapid GnRH-R desensi tization occurs at a level beyond both the receptor and phospholipase C (PLC) activation. These events were receptor specific and not relate d to cell type, since similar rapid desensitization profiles were obse rved in both GnRH-R expressing pituitary and nonpituitary cell types. In contrast, profiles of GnRH-stimulated calcium responses were cell t ype specific.