Novel progesterone receptors: neural localization and possible functions

Abstract

Progesterone (P4) regulates a wide range of neural functions and likely acts through multiple receptors. Over the past 30 years, most studies investigating neural effects of P4 focused on genomic and non-genomic actions of the classical progestin receptor (PGR). More recently the focus has widened to include two groups of non-classical P4 signaling molecules. Members of the Class II progestin and adipoQ receptor (PAQR) family are called membrane progestin receptors (mPRs) and include: mPRα (PAQR7), mPRβ (PAQR8), mPRγ (PAQR5), mPRδ (PAQR6), and mPRε (PAQR9). Members of the b5-like heme/steroid-binding protein family include progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin. Results of our recent mapping studies show that members of the PGRMC1/S2R family, but not mPRs, are quite abundant in forebrain structures important for neuroendocrine regulation and other non-genomic effects of P4. Herein we describe the structures, neuroanatomical localization, and signaling mechanisms of these molecules. We also discuss possible roles for Pgrmc1/S2R in gonadotropin release, feminine sexual behaviors, fluid balance and neuroprotection, as well as catamenial epilepsy.

Progesterone Receptor Membrane Component 1 Is a Functional Part of the Glucagon-like Peptide-1 (GLP-1) Receptor Complex in Pancreatic β Cells

“…The Role of PGRMC1 in Modulating Insulin Secretion in Pancreatic ␤ Cells-As mentioned, PGRMC1 belongs to the MAPR family (39) and binds progesterone with high affinity in mammalian cells. It also has the ability to bind other molecules, including testosterone, glucocorticoids, heme, and cholesterol metabolites (32,33).…”

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

“…IRE1 inhibition also upregulates the expression level of PGRMC2, a potential downstream eff ector of FOXM1 transcription factor, which plays important roles in the tumorigenesis and tumor metastasis in multiple human carcinomas as tumor suppressor and migration inhibitor (Wendler and Wehling 2013;Petersen et al 2013;Ye et al 2015). Another estrogen-responsive protein, TRIM16, which inhibits hepatocellular carcinoma cell migration and invasion by suppression of ZEB2 expression as well as suppresses cancer cell viability by involving interaction and stabilization of TDP43 with consequent eff ects on E2F1 and pRb proteins (Kim et al 2016), is also up-regulated in glioma cells without IRE1 signaling enzyme function.…”

“…Pedram et al (2006) have shown that in the mitochondria of MCF-7 breast cancer cells and endothelial cells there are high-affi nity estrogen receptors, which impact mitochondrial functions and control the survival of the tumor cells. PGRMC2 (progesterone receptor membrane component 2) also known as steroid receptor protein DG6 and progesterone membrane binding protein (PMBP), is a member of non-classical progesterone signaling molecules (membrane progestin receptors) and a potential downstream eff ector of FOXM1 transcription factor, which plays important roles in tumorigenesis and tumor metastasis in multiple human carcinomas as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 proteins (Petersen et al 2013;Wendler and Wehling 2013;Ye et al 2015).…”

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

“…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 .…”

“…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.…”