Participation of membrane progesterone receptor α in the inhibitory effect of progesterone on prolactin secretion

Abstract

The membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ and mPRε) are known to mediate rapid nongenomic progesterone functions in different cell types. However, the functions of these receptors in the pituitary have not been reported to date. In the present study, we show that the expression of mPRα was the highest among the mPRs in the rat anterior pituitary gland. Immunostaining of mPRα was detected in somatotrophs, gonadotrophs and lactotrophs. Interestingly, 63% of mPRα-positive cells within the pituitary were lactotrophs, suggesting that mPRα is involved in controlling prolactin (PRL) secretion in the pituitary. To test this hypothesis, rat pituitaries were incubated (1 hour) with either progesterone (P4) or the mPRα-specific agonist Org OD 02-0. PRL secretion was then measured by radioimmunoassay. The results of this experiment revealed that both P4 and Org OD 02-0 decreased PRL secretion. Moreover, the results from the GH3 cell line (CCL-82.1) showed that P4 and Org OD 02-0 inhibited PRL release, although the nuclear PR agonist R5020 was ineffective. Our investigation of the cellular mechanisms behind mPRα activity indicated that both P4 and Org OD 02-0 decreased cAMP accumulation, whereas R5020 was ineffective. In addition, the Org OD 02-0-effect on PRL release was blocked by pretreatment with pertussis toxin, an inhibitor of Go/Gi proteins. Because transforming growth factor (TGF)β1 is a potent inhibitor of PRL secretion in lactotrophs, we lastly evaluated whether TGFβ1 was activated by progesterone and whether this effect was mediated by mPRα. Our results showed that P4 and Org OD 02-0, but not R5020, increased active TGFβ1 levels. This effect was not observed when cells were transfected with mPRα-small interfering RNA. Taken together, these data provide new evidence suggesting that mPRα mediates the progesterone inhibitory effect on PRL secretion through both decreases in cAMP levels and activation of TGFβ1 in the lactotroph population.

Biomarker Discovery for Immunotherapy of Pituitary Adenomas: Enhanced Robustness and Prediction Ability by Modern Computational Tools

“…Since the upregulated expression of immunosuppressive protein PD-L1 was observed in the pituitary gland of PA patients [43], the inhibition of LMO4/STAT3/PD-L1 signaling could block the immune evasion by recovering the recognition and elimination of cancer cells via CD8 + lymphocytes [48]. Furthermore, the transforming growth factor-beta ( TGFB ) was reported to be one of the chief immune suppressive mediators of PRL secretion and PA proliferation [49,50]. Its receptor, TGFBR3 , was also discovered in this study as a DEG, which could be another target candidate for developing novel PA immunotherapy.…”

“…Increased levels (both mRNA and protein) of programmed death-ligand 1 ( PD-L1 , the immunosuppressive protein) are observed in tumor tissue of PA patients [43], which can induce immune evasion by desensitizing the recognition and elimination of cancer cells via CD8 + lymphocytes [48]. Transforming growth factor-beta ( TGFB ) was discovered as one of the chief immune suppressive mediators of prolactin (PRL) secretions and PA proliferation [49,50]. Apart from the above studies, a variety of transcriptomics analyses (demonstrated in Table 1) have been conducted to identify the differentially expressed genes (DEGs) between PA patients and normal ones [51,52,53,54].…”

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

“…mPRs mediate rapid, non-classical progesterone actions, which are frequently non-genomic, by activating G proteins and modulation of intracellular signaling pathways. The five mPR members of the PAQR family, mPRα (PAQR7), mPRβ (PAQR8), mPRγ (PAQR5), mPRδ (PAQR6), and mPRε (PAQR9), have different tissue distributions, progestin binding (32,33), relaxation of human myometrial and vascular muscle cells (34,35), reversal of epithelial to mesenchymal transition in breast cancer cells (36), and inhibition of prolactin release from rat lactotrophs through activation of TGFβ1 (37).…”

“…mPRα is the predominant mPR isoform expressed in most progesterone target tissues with the exception of the brain and is the primary mPR that regulates several critical reproductive and non-reproductive progestin functions. For example, mPRα mediates oocyte meiotic maturation and sperm motility in fish, anti-apoptosis in fish ovarian granulosa cells and in human breast cancer cells ( 32 , 33 ), relaxation of human myometrial and vascular muscle cells ( 34 , 35 ), reversal of epithelial to mesenchymal transition in breast cancer cells ( 36 ), and inhibition of prolactin release from rat lactotrophs through activation of TGFβ1 ( 37 ).…”

“…Knockdown of mPRβ and mPRα mRNAs in the midbrains of female adult rodents by injection of antisense oligonucleotides into the lateral ventricle decreased reproductive behaviors (lordosis and aggression/rejection), whereas other behaviors were not affected ( 10 , 46 ). The mPR agonist, 02-0, increases dopamine release from hypothalamic explants of rodent prolactinoma models resulting in decreased prolactin secretion and also exerts a direct action on mPRα in pituitary lactotrophs to decrease prolactin secretion through TGFβ-1 ( 37 , 38 ). These results suggest mPR agonists are potentially of therapeutic use for treating pathological hyperprolactinemia ( 47 ).…”