Luteinizing hormone-releasing hormone antagonist Cetrorelix regulates the expression of Galphas and Galphai protein subunits and adenylate cyclase activity in rat ovary, breast and pituitary.
The mechanisms by which luteinizing hormone-releasing hormone (LH-RH) antagonists act on extra-pituitary tissues are poorly understood. In view of extensive use of Cetrorelix in gynecology and oncology, we investigated its effects on signal transduction pathways of G-protein coupled receptors and adenylate cyclase which are involved in a huge array of cellular events including normal and pathological cell proliferation. Thirty days after a single i.m. injection of 3 mg Cetrorelix pamoate depot to female rats, normal or ovariectomized, we evaluated the effects of this chronic treatment on the expression of alphas and alphai G-protein subunits in the ovary, breast and pituitary, as well as the adenylate cyclase response in vitro to LH-RH, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP). Varied patterns of response to Cetrorelix, depending on the gland and estrogenic status were observed. Western blot analysis showed a modest decrease of alphas and a modest increase of alphai G-protein subunit levels in ovary, a marked increase of alphas and alphai levels in breast, and a lack of effect on alphas/alphai levels in pituitary. In the ovary, adenylate cyclase activity was not changed by in vitro addition of LH-RH, but the responses to VIP and PACAP increased after Cetrorelix treatment. In the breast, chronic administration of the LH-RH antagonist decreased the adenylate cyclase response to PACAP, which returned to normal after ovariectomy. In the pituitary, Cetrorelix abolished the stimulatory effect of VIP upon adenylate cyclase activity. Thus, the LH-RH antagonist Cetrorelix exerted selective modifications at different steps of the G-protein coupled receptors/adenylate cyclase system of signal transduction in the rat ovary, breast and pituitary.
Collado
Beatriz
B
Department of Biochemistry and Molecular Biology, University of Alcalá, Spain.
Carmena
María J
MJ
Cortés
Joaquín
J
Schally
Andrew V
AV
Prieto
Juan C
JC
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism*; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D009479:Neuropeptides / Q000378:metabolism; D010053:Ovary / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D010902:Pituitary Gland / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
C495403:Adcyap1 protein, rat; D006727:Hormone Antagonists; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D007987:Gonadotropin-Releasing Hormone; D014660:Vasoactive Intestinal Peptide; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; C062876:cetrorelix