Homologous down-regulation of gonadotropin-releasing hormone receptor sites and messenger ribonucleic acid transcripts in alpha T3-1 cells.

Abstract

GnRH is known to down-regulate its pituitary receptors by mechanisms that include endocytosis of the agonist-receptor complex. To evaluate the extent to which changes in receptor synthesis contribute to this process, the effects of GnRH and its analogs on GnRH receptor number and messenger RNA (mRNA) levels were analyzed in the alpha T3-1 gonadotroph cell line. Treatment with GnRH or its potent agonist analog, des-Gly10-[D-Ala6]GnRH N-ethylamide, reduced GnRH receptor number in a time- and dose-dependent manner, with a half-maximal decrease in response to 10(-6) M GnRH or agonist analog by 75 min. The maximum decrease in receptor number (to 31% of the control value) was sustained for up to 72 h. In alpha T3-1 cells incubated with 10(-8) M GnRH or agonist analog, the GnRH receptors fell by 28% and 46% after 2 h, respectively; no change in receptors occurred after treatment with 10(-8) M GnRH antagonist ([D-pGlu1,D-Phe2,D-Trp3,6]GnRH). Time- and dose-dependent reductions in the level of receptor mRNA were also observed after treatment of alpha T3-1 cells with GnRH and the agonist analog. However, the maximal reduction in mRNA levels (to 60-70% of the control value) was consistently less than the decline in receptor number. These results indicate that the mechanism of GnRH receptor down-regulation in alpha T3-1 gonadotrophs includes reduction of receptor synthesis secondary to decreases in receptor mRNA levels. The finding that reductions in mRNA levels were relatively less than the decreases in receptor number is consistent with the involvement of additional mechanisms, including endocytosis and degradation, in down-regulation of the GnRH receptor.

Molecular structure of the human gonadotropin-releasing hormone receptor gene

“…This cell line was obtained by targeted tumorigenesis in the mouse pituitary with SV40 large antigen driven by human glycoprotein hormone a-subunit promoter (51). It has been used to study many aspects of gonadotrope physiology, including GnRH receptor regulation (52)(53)(54). Our results clearly demonstrated ( (Fig.…”

Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH

“…Much evidence indicates that the receptor number is regulated at the pretranslational level by LH-RH-R gene expression (26,35), but data on the posttranscriptional regulation by recycling, modification, or degradation have also been reported (12).…”

“…A dramatic increase in the mRNA expression of pituitary LH-RH-R can be induced by ovariectomy (12). It is well known that the elimination of the negative feedback of ovarian steroid hormones on the hypothalamus by ovariectomy causes an increase in the pulsatile LH-RH release from hypothalamic neurons and a marked elevation in the LH-RH concentration in the pituitary portal vessels (36).…”

“…An intermittent administration of native LH-RH or LH-RH agonists in vivo and in vitro, mimicking the natural pulsatile release of this neuropeptide from the hypothalamus, stimulates the synthesis and the release of gonadotropins and leads to an increase in the number of its receptors (11). However, continuous administration of LH-RH and its agonists, especially at high concentration, causes a downregulation of receptors and desensitization of gonadotrophs (11)(12)(13). Thus, administration of depot preparations of LH-RH agonists results in the suppression of the secretion of gonadotropins and sex hormones which provides the basis for clinical applications of this class of compounds (1,2,14).…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…It is a remarkable feature of GnRH receptors that they undergo desensitisation after initial augmentation if they are stimulated by continuous GnRH administration [109,115,116], which has a therapeutic role for the treatment of prostate cancer [117]. Evidence from animal studies has shown that kisspeptins exhibit pulsatile secretion within the hypothalamus [108] and continuous Kp-10 stimulation leads to desensitisation of kisspeptin receptors as shown by an initial rise in LH levels followed by a rapid drop to baseline levels [118][119][120][121].…”