Gonadotropin-releasing hormone-desensitized LbetaT2 gonadotrope cells are refractory to acute protein kinase C, cyclic AMP, and calcium-dependent signaling.
Sustained exposure of gonadotropes to GnRH causes a pronounced desensitization of gonadotropin release, but the mechanisms involved are poorly understood. It is known that desensitization is associated with decreased GnRH receptor and Gq/11 levels in alphaT3-1 cells, but it is not known whether downstream signaling is impaired. We have shown previously that chronic stimulation of signaling via expression of an active form of Galphaq causes GnRH resistance in LbetaT2 cells. In this study we investigated whether chronic GnRH treatment could down-regulate protein kinase C (PKC), cAMP, or Ca2+-dependent signaling in LbetaT2 cells. We found that chronic GnRH treatment desensitizes cells to acute GnRH stimulation not only by reducing GnRH receptor and Gq/11 expression but also by down-regulating PKC, cAMP, and calcium-dependent signaling. Desensitization was observed for activation of ERK and p38 MAPK and induction of c-fos and LHbeta protein expression. Activation of individual signaling pathways was able to partially mimic the desensitizing effect of GnRH on ERK, p38 MAPK, c-fos, and LHbeta but not on Gq/11. Chronic stimulation with phorbol esters reduced GnRH receptor expression to the same extent as chronic GnRH. Sustained GnRH also desensitized PKC signaling by down-regulating the delta, epsilon, and theta isoforms of PKC. We further show that chronic GnRH treatment causes heterologous desensitization of other Gq-coupled receptors.
Liu
Fujun
F
Department of Medicine, University of California San Diego Cancer Center, San Diego, California 92093, USA.
Austin
Darrell A
DA
Webster
Nicholas J G
NJ
D000818:Animals; D020013:Calcium Signaling; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006062:Gonadotropins / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D037101:Luteinizing Hormone, beta Subunit / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D006062:Gonadotropins; D007527:Isoenzymes; D037101:Luteinizing Hormone, beta Subunit; D016760:Proto-Oncogene Proteins c-fos; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D000242:Cyclic AMP; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate