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      Novel progesterone receptors: neural localization and possible functions

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          Abstract

          Progesterone (P 4) regulates a wide range of neural functions and likely acts through multiple receptors. Over the past 30 years, most studies investigating neural effects of P 4 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 P 4 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 P 4. 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.

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          Most cited references98

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          Progesterone receptor membrane component 1: an integrative review.

          Progesterone receptor membrane component 1 (PGRMC1) contains a cytochrome b5 domain fold and belongs to the so-called membrane-associated progesterone receptor (MAPR) protein family that is widespread in eukaryotes. PGRMC1 and the related PGRMC2 mammalian family member diverged sometime after the evolution of segmented metazoan body plan and the appearance of vertebrates. Therefore PGRMC1 might be expected to be involved in some ancient eukaryotic processes, as well as more modern functions related to multicellularity and tissue interactions. Perhaps this explains the perplexing diversity of contexts where PGRMC1 has been observed, apparently being involved in different cellular processes at various sub-cellular locations. This review attempts to collate and interpret these observations. Ironically, despite being the archetypal member of the MAPR family, it has yet to be demonstrated that PGRMC1 exhibits specific progesterone binding. Potential roles of heme and steroid/sterol ligands are reviewed, as well as the implications of apparent target sequences within PGRMC1 for binding by SH2- and SH3-domain proteins as well as kinases. These motifs are modelled using the cytochrome b5 domain NMR structure of the Arabidopsis protein 1J03, implicating a possible function for PGRMC1 as an adaptor protein involved in regulating protein interactions and intracellular signal transduction and/or membrane trafficking. This interpretation is supported by the apparent presence of immunoreceptor tyrosine-based activation motif/ITAM sequences that are involved in endocytosis and vesicle targeting, and the colocalisation of PGRMC1 with caveolin and at the cytoplasmic membrane. Evidence for roles in disease, especially cancer, is also discussed.
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            Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site

            The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumor cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor binding site. WC-21, a sigma-2 ligand containing both a photoactive moiety azide and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was then identified as PGRMC1 (progesterone receptor membrane component-1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalizes with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.
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              PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding.

              Hormone signaling is important in a number of disease states, and hormone receptors are effective therapeutic targets. PGRMC1 (progesterone receptor membrane component 1) is a member of a multi-protein complex that binds to progesterone and other steroids, as well as pharmaceutical compounds. In spite of its name, PGRMC1 shares homology with cytochrome b5-related proteins rather than hormone receptors, and heme binding is the sole biochemical activity of PGRMC1. PGRMC1 and its homologues regulate cholesterol synthesis by activating the P450 protein Cyp51/lanosterol demethylase, and the cholesterol synthetic pathway is an important target in cardiovascular disease and in treating infections. PGRMC1 binding partners include multiple P450 proteins, PAIR-BP1, Insig, and an uncharacterized hormone/drug-binding protein. PGRMC1 is induced in a spectrum of cancers, where it promotes cell survival and damage resistance, and PGRMC1 is also expressed in the nervous system and tissues involved in drug metabolism, cholesterol synthesis and hormone synthesis and turnover. One of the appealing features of PGRMC1 and its associated protein complex is its affinity for steroids and drugs. Together with its biological role in promoting tumor survival, PGRMC1 is an attractive target for therapeutic intervention in cancer and related malignancies.
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                Author and article information

                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                21 June 2013
                19 September 2013
                2013
                : 7
                : 164
                Affiliations
                [1] 1Molecular and Cellular Neuroendocrinology, Department of Veterinary and Animal Sciences, University of Massachusetts Amherst Amherst, MA, USA
                [2] 2Department of Psychology, University of Vermont Burlington, VT, USA
                [3] 3Toxicology and Pharmacology Department, Complutense University of Madrid Madrid, Spain
                [4] 4Department of Physiology and Pharmacology, Center for Neuroscience, West Virginia University Morgantown, WV, USA
                Author notes

                Edited by: John J. Peluso, University of Connecticut Health Center, USA

                Reviewed by: Cynthia L Bethea, Oregon Health & Science University, USA; Paul S. Cooke, University of Florida, USA

                *Correspondence: Sandra L. Petersen, Molecular and Cellular Neuroendocrinology, Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, 661 N Pleasant, Amherst, MA 01003, USA e-mail: spetersen@ 123456vasci.umass.edu

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience.

                Article
                10.3389/fnins.2013.00164
                3776953
                24065878
                66587b28-9394-4e65-909d-08826330bf4c
                Copyright © 2013 Petersen, Intlekofer, Moura-Conlon, Brewer, Del Pino Sans and Lopez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 May 2013
                : 24 August 2013
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 95, Pages: 7, Words: 6799
                Categories
                Endocrinology
                Review Article

                Neurosciences
                pgr,pgrmc1,25dx,paqr,mpr
                Neurosciences
                pgr, pgrmc1, 25dx, paqr, mpr

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