Rapid down-regulation of the type I inositol 1,4,5-trisphosphate receptor and desensitization of gonadotropin-releasing hormone-mediated Ca2+ responses in alpha T3-1 gonadotropes

Despite no evidence for desensitization of phospholipase C-coupled gonadotr opin-releasing hormone (GnRH) receptors, we previously reported marked supp ression 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 ino sitol 1,4,5-trisphosphate (Ins(1,4,5)P-3) responses, thereby implicating un coupling 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 Forre st-Owen, W. (1996) J. Biol. Chem. 271, 23711-23117). In the current study w e demonstrate that GnRH causes a homologous and heterologous desensitizatio n 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 contribute s to a fast, profound, and sustained loss of Ins(1,4,5)P-3 receptor immunor eactivity. These data highlight a potential role for rapid Ins(1,4,5)P-3 re ceptor down-regulation in homologous and heterologous desensitization and i n particular suggest that this mechanism may contribute to the suppression of the reproductive system that is exploited in the major clinical applicat ions of GnRH analogues.