Rapid down-regulation of the type I inositol 1,4,5-trisphosphate receptor and desensitization of gonadotropin-releasing hormone-mediated Ca2+ responses in αT3-1 gonadotropes

Despite no evidence for desensitization of phospholipase C-coupled gonadotropin-releasing hormone (GnRH) receptors, we previously reported marked suppression of GnRH-mediated Ca2+ responses in alpha T3-1 cells by pre-exposure to GnRH. This suppression could not be accounted for solely by reduced inositol 1,4,5-trisphosphate (Ins(1,4,5)P-3) responses, thereby implicating uncoupling of Ins(1,4,5)P-3 production and Ca2+ mobilization (McArdle, C. A., Willars, G. B., Fowkes, R, C., Nahorski, S. R., Davidson, J. S., and Forrest-Owen, W. (1996) J. Biol. Chem. 271, 23711-23117). In the current study we demonstrate that GnRH causes a homologous and heterologous desensitization of Ca2+ signaling in alpha T3-1 cells that is coincident with a rapid (t(1/2) < 20 min), marked, and functionally relevant loss of type I Ins(1,4,5)P-3 receptor immunoreactivity and binding. Furthermore, using an <alpha>T3-1 cell line expressing recombinant muscarinic M, receptors we show that the unique resistance of the GnRH receptor to rapid desensitization contributes to a fast, profound, and sustained loss of Ins(1,4,5)P-3 receptor immunoreactivity. These data highlight a potential role for rapid Ins(1,4,5)P-3 receptor down-regulation in homologous and heterologous desensitization and in particular suggest that this mechanism may contribute to the suppression of the reproductive system that is exploited in the major clinical applications of GnRH analogues.