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

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 [³H]-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.

Rethinking progesterone regulation of female reproductive cyclicity

“…Evidence exists for progesterone acting independent of its nuclear receptor, PGR (23,24). As a consequence, we examined the actions of exogenous progesterone treatment on cyclicity.…”

Molecular approaches related to the European eel (Anguilla anguilla) reproductive process

“…In the brain and pituitary, mRNAs for all five mPR subtypes were constantly expressed during spermatogenesis. mPRγ, mPRAL1 and mPRAL2 showed low expression in all the brain parts and the pituitary, whereas mPRα was highly expressed; and mPRδ showed the greatest brain expression, like in human brain (Thomas et al, 2012;Pang et al, 2013). In human, the mPRs seem to be involved in the negative feedback of progesterone on the gonadotropin-releasing hormone secretion (Sleiter et al, 2009;Thomas et al, 2012), while further research is required to elucidate the specific signalling roles of mPRs in the eel brain and pituitary.…”

“…The mPRs belong to the progestin and adipoQ receptor (PAQR) family. This family includes five mPR subtypes: mPRα (PAQR7) first identified and characterized in spotted seatrout (Cynoscion nebulosus (Zhu et al, 2003b), mPRβ (PAQR8) and mPRγ (PAQR5) identified and characterized in humans and other vertebrates (Zhu et al, 2003a), mPRδ (PAQR6) and mPRε (PAQR9), which respond to progestins in yeast recombinant expression systems (Thomas et al, 2012;Pang et al, 2013;Smith et al, 2008), together with PAQR3, PAQR4, two adiponectin receptors (ADR1 and ADR2) and two monocyte to macrophage differentiation proteins (MMD, MMD2) (Thomas et al, 2007). In the present study, phylogenetic analyses including PAQR3 to PAQR9 were performed in order to determine the relationship of eel mPRs characterized with other PAQR forms.…”

“…Evidence has been obtained that steroid hormones, thyroid hormones, and vitamin D, similarly to water soluble signalling molecules, exert this rapid cell surface-initiated hormone action through binding to membrane receptors, which lead to the activation of intracellular second messenger pathways (Revelli et al, 1998;Watson et al, 1999;Falkenstein et al, 2000;Norman et al, 2004). The mPRs were first discovered and characterized in fish ovaries (Zhu et al, 2003a), and five isoforms (mPRα, mPRβ, mPRγ, mPRδ, mPRε) were subsequently identified in humans and other vertebrates (Zhu et al, 2003b;Thomas et al, 2012;Peterson et al, 2013). Both nPRs and mPRs are highly expressed in testis (Ikeuchi et al, 2002;Hanna et al, 2009) and brain (Thomas et al, 2012;Peterson et al, 2013), but the functions mediated by them are still unclear.…”

“…The mPRs were first discovered and characterized in fish ovaries (Zhu et al, 2003a), and five isoforms (mPRα, mPRβ, mPRγ, mPRδ, mPRε) were subsequently identified in humans and other vertebrates (Zhu et al, 2003b;Thomas et al, 2012;Peterson et al, 2013). Both nPRs and mPRs are highly expressed in testis (Ikeuchi et al, 2002;Hanna et al, 2009) and brain (Thomas et al, 2012;Peterson et al, 2013), but the functions mediated by them are still unclear. In Japanese eel, progestin receptor 1 (pgr1) is expressed in testis germ cells, Sertoli cells, and testis interstitial cells, whereas progestin receptor 2 (pgr2) mRNA has been detected only in testis germ cells .…”