Candidates for membrane progestin receptors—Past approaches and future challenges

Abstract

Progestins have a broad range of functions in reproductive biology. Many rapid nongenomic actions of progestins have been identified, including induction of oocyte maturation, modulation of reproductive signaling in the brain, rapid activation of breast cancer cell signaling, induction of the acrosomal reaction and hypermotility in mammalian sperm. Currently, there are three receptor candidates for mediating rapid progestin actions: (1) membrane progestin receptors (mPRs); (2) progestin receptor membrane components (PGRMCs); and (3) nuclear progestin receptors (nPRs). The recently-described mPR family of proteins has seven integral transmembrane domains and mediates signaling via G-protein coupled pathways. The PGRMCs have a single transmembrane with putative Src homology domains for potential activation of second messengers. The classical nPRs, in addition to having well defined transcriptional activity, can also mediate rapid activation of intracellular signaling pathways. However, details of the mechanisms by which these three classes of progestin receptors mediate rapid intracellular signaling and their subcellular localization remain unclear. In addition, mPRs, nPRs and PGRMCs exhibit overlapping expression and functions in multiple tissues, implying potential interactions during oocyte maturation, parturition, and breast cancer signaling in individual cells. However, the overwhelming majority of studies to date have focused on the functions of one of these groups of receptors in isolation. This review will summarize recent findings on the three major progestin receptor candidates, emphasizing the different approaches used, some experimental pitfalls, and current controversies. We will also review evidence for the involvement of mPRs and nPRs in one of the most well-characterized nongenomic steroid actions in basal vertebrates, oocyte maturation, and conclude by suggesting some future areas of research. Clarification of the controversies surrounding the identities and localization of membrane progestin receptors may help direct future research that could advance our understanding of rapid actions of steroids.

Introduction

Nuclear steroid receptors (nSR) are primarily localized in the nucleus or cytoplasm of cells. These intracellular receptors are activated by the binding of steroids, which are hydrophobic and freely diffuse through the cell membrane. The ligand-receptor complex is translocated to the nucleus, where it binds to hormone response elements on genes, resulting in changes in their rates of transcription and translation. This classical genomic mechanism of steroid action, involving the transcription of DNA and synthesis of proteins, is a relatively slow process that can take hours to days to elicit a biological response. However, unlike the classical steroid mechanism, many actions of steroids occur much more rapidly (< 30 min) and in the presence of inhibitors of transcription and translation. These rapid, nongenomic or nonclassical steroid actions have been well recognized and extensively studied over the past few decades (Pietras and Szego, 1975, Norman et al., 2004, Thomas, 2008).

Nonclassical rapid steroid actions have been demonstrated for all the major classes of steroids (Norman et al., 2004). Well known examples of nonclassical progestin actions include induction of the acrosomal reaction in sperm (Blackmore et al., 1990, Sabeur et al., 1996, Baldi et al., 1998, Luconi et al., 2004), rapid increases in sperm motility (Thomas et al., 2005), modulation of gonadotropin-releasing hormone discharge in the brain (Majewska et al., 1986, Calogero et al., 1998, Sim et al., 2001), rapid activation of breast cancer cell signaling (Faivre et al., 2005), and resumption of oocyte maturation in fish and amphibian species (Kostellow et al., 1980, Ferrell, 1999, Thomas et al., 2002). Interestingly, some of these actions occur in the absence of the nuclear progesterone receptor (nPR). For example, progestins activate signal transduction pathways in human T lymphocytes and Jurkat cells that lack nPR (Dosiou et al., 2008). In addition, rapid behavioral responses to progesterone such as lordosis persist in nPR-null mice (Frye et al., 2006). Rapid, nongenomic actions of progestins on gametes have been investigated extensively (Maller, 2001, Thomas et al., 2004). Furthermore, specific steroid binding sites have been identified on plasma membranes prepared from oocytes and sperm implying membrane localization and activity of progestin receptors (Patiño and Thomas, 1990, Blackmore and Lattanzio, 1991). Although these studies have provided strong evidence for the existence of specific membrane receptors, the identities of progestin receptors mediating these effects remain controversial (Lösel et al., 2003, Norman et al., 2004, Thomas, 2008).

In this paper we will review the following major candidates for progestin receptors mediating the nongenomic actions of progestins, with an emphasis on their effects on gametes: (1) membrane progestin receptors (mPRs) (Zhu et al., 2003a, Zhu et al., 2003b); (2) progesterone receptor membrane component 1 (PGRMC1) (Falkenstein et al., 1996, Meyer et al., 1996); and (3) nuclear progestin receptors (nPRs) (Bayaa et al., 2000, Tian et al., 2000). For information on steroid receptor candidates mediating nongenomic actions of other steroids, please refer to other recent reviews (Hammes and Levin, 2007, Stormshak and Bishop, 2008). Approaches used in the past to identify and characterize membrane progestin receptors, and the controversies surrounding their identities, localization and signaling will be reviewed. In addition, evidence in support of mPRs and nPRs as the receptors mediating the effects of maturation-inducing steroids on oocyte maturation in basal vertebrates is discussed.