Desensitization of cultured pituitary cells to gonadotropin-releasing hormone: evidence for a post-receptor mechanism.
Previous reports have demonstrated that chronic exposure to high concentrations of gonadotropin-releasing hormone (GnRH) induces a state of refractoriness to GnRH in the pituitary. In order to determine the role of the GnRH receptor in desensitization, we have compared the ability of GnRH to stimulate luteinizing hormone (LH) secretion with changes in GnRH binding. Cultured rat anterior pituitary cells exposed to 1 nM GnRH for 12 h became refractory to this dose of GnRH but were able to release LH in response to higher concentration of GnRH. Exposure to 1 nM or 10 nM GnRH not only caused a shift in the EC50 of GnRH to release LH from 0.28 nM to about 4.5 nM, but also produced a decrease in the maximal response which could not be fully explained by the reduced LH cell content. Examination of GnRH receptor binding to cells pretreated with similar doses of GnRH revealed no change in receptor affinity and a 10-90% increase in receptor number. This paradoxical up-regulation of GnRH receptor number occurred over a period of 6 h and was completely abolished in the presence of cycloheximide. The continuous presence of GnRH was not required for receptor up-regulation since pulses of GnRH were just as effective in increasing GnRH binding. The results indicate that changes in GnRH receptor affinity and number do not always parallel the changes in pituitary responsiveness to GnRH. Therefore, GnRH-induced desensitization cannot be fully explained by down-regulation of receptors and must involve a post-receptor mechanisms.
D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects*; D010906:Pituitary Hormone-Releasing Hormones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000032:analysis / Q000187:drug effects*; D011966:Receptors, LHRH
D010906:Pituitary Hormone-Releasing Hormones; D011956:Receptors, Cell Surface; D011966:Receptors, LHRH; D007986:Luteinizing Hormone; D003513:Cycloheximide