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Review
, 96 (2), 162-71

Membrane Progesterone Receptors: Evidence for Neuroprotective, Neurosteroid Signaling and Neuroendocrine Functions in Neuronal Cells

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Review

Membrane Progesterone Receptors: Evidence for Neuroprotective, Neurosteroid Signaling and Neuroendocrine Functions in Neuronal Cells

Peter Thomas et al. Neuroendocrinology.

Abstract

Membrane progesterone receptors (mPRs) are novel G protein-coupled receptors belonging to the progestin and adipoQ receptor family (PAQR) that mediate a variety of rapid cell surface-initiated progesterone actions in the reproductive system involving activation of intracellular signaling pathways (i.e. nonclassical actions). The mPRs are highly expressed in the brain, but research on their neural functions has only been conducted in a single neuronal cell line, GT1-7 cells, which have negligible nuclear progesterone receptor (PR) expression. GT1-7 cells express mPRα and mPRβ on their plasma membranes which is associated with the presence of high-affinity, specific [(3)H]-progesterone receptor binding. The neurosteroid, allopregnanolone, is an effective ligand for recombinant mPRα with a relative binding affinity of 7.6% that of progesterone. Allopregnanolone acts as a potent mPR agonist on GT1-7 cells, mimicking the progesterone-induced decrease in cAMP accumulation and its antiapoptotic actions at low nanomolar concentrations. The decrease in cAMP levels is associated with rapid progesterone-induced downregulation of GnRH pulsatile secretion from perifused GT1-7 cells. The recent suggestion that mPRs are alkaline ceramidases and mediate sphingolipid signaling is not supported by empirical evidence that TNFα does not bind to mPRs overexpressed in human cells and that exogenous sphingomyelinase is ineffective in mimicking progestin actions through mPRs to induce meiotic maturation of fish oocytes. Taken together, these recent studies indicate that mPRs mediate neuroprotective effects of progesterone and allopregnanolone and are also the likely intermediaries in progesterone-induced inhibition of pulsatile GnRH secretion in GT1-7 cells.

Figures

Figure 1
Figure 1
The mPRs are expressed in mouse neuronal GT1-7 cells (A) and low nanomolar concentrations of allopregnanolone mimic the inhibitory effects of progesterone on cAMP production (B), cell death (C) and DNA fragmentation (D) in neuronal GT1-7 cells. (A) Detection of mPRα, mPRβ, mPRδ and mPRε mRNAs by RT-PCR. (B) Cultured mouse neuronal GT1-7 cells were incubated overnight in serum-free media to reduce background adenylyl cyclase activity before treatment for 15 min. with vehicle, progesterone or allopregnanolone (20 nM and100 nM). The cAMP concentrations in cell lysates were measured with an EIA kit (Cayman, Ann Arbor, MI). (C,D) Cells, 70% confluent, were cultured for 4 days in serum-free media alone (vehicle) of media containing progesterone or allopreganolone. Approximately 500 cells were counted for cell death and DNA fragmentation after staining with trypan blue and by TUNEL assay, respectively, as described previously [45]. Veh: vehicle, P4: progesterone, A: allopregnanolone. N=6. * P<0.05, ** P<0.001 compared to vehicle controls (one-way ANOVA and Tukey’s ).
Figure 2
Figure 2
The proposed role of mPRs in sphingolipid signaling is not supported by empirical data showing a lack of TNFα binding to mPRs (A–C) and the ineffectiveness of exogenous neutral sphingomyelinase in inducing meiotic maturation of zebrafish oocytes (D). A–C, Single point competition with 1μM progesterone (P4), 4μg/ml TNFα or 4μg/ml adiponectin (adip) for [3H]-progesterone binding to plasma membranes of MDA-MB-231 breast cancer cells over expressing mPRα (A), mPRβ (B), or mPRγ (C). Data represent mean disintegrations per minute (DPM)/50μg protein ± SEM, n=3; **, P < 0.0001 compared with vehicle (veh) control by one-way ANOVA and Dunnett’s multiple comparison test. D, Comparison of the effects of exogenous B. cerus spingomyelinase (SMase, 0.5 and 1.0 U/ml) and 17,20β-dihydroxy-4-pregene-3-one (DHP, 20 and 50 nM) on percent GVBD of denuded zebrafish oocytes. Large, fully grown zebrafish oocytes (diameter> 550μm) were denuded and the oocytes (30–40 oocytes/1 ml Leibovitz L-15 medium/well, 4 wells/treatment) were incubated with the various treatments for 3 hrs and scored at the end of the incubation period for germinal vesicle breakdown (GVBD) as described previously [91]. Data represent mean % oocytes completing GVBD ± SEM, n=4; *, P < 0.05 compared with vehicle (veh) control by one-way ANOVA and Dunnett’s multiple comparison test.

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