Membrane Progestin Receptors: Beyond the Controversy, Can We Move Forward?
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Article in press - uncorrected proof BioMol Concepts, Vol. 1 (2010), pp. 41–47 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BMC.2010.001 Review Membrane progestin receptors: beyond the controversy, can we move forward? Amel Salhi, Julie Lemale, Nicolas Paris, May also been reported to have biological effects within minutes, Bloch-Faure and Gilles Crambert* as well as effects in cells or tissues devoid of their specific nuclear receptors. These rapid and non-classical effects were UPMC Univ Paris 6/INSERM/CNRS, Centre de Recherche originally described for progesterone (1) and then reported des Cordeliers, UMRS 872 Equipe 3 Laboratoire de for all major classes of steroids (2, 3), and particularly for Ge´nomique, Physiologie et Physiopathologie Re´nales progesterone in various physiological contexts such as ERL 7226, F-75006, Paris, France oocyte maturation (4), induction of acrosomal reaction in * Corresponding author sperm wfor review see Ref. (5)x, and activation of calcium e-mail: [email protected] uptake by renal proximal tubules (6, 7). Many explanations have been put forward to support these observations wfor review see Ref. (8) and Figure 1x: (i) the disturbance of the Abstract membrane fluidity by insertion of a lipophilic molecule in the lipid bilayer which can then influence activity of trans- Steroids are well-known mediators of many different physi- porters, channels etc.; (ii) the action of nuclear receptors at ological functions. Their best characterized mechanism of the plasma membrane; (iii) the action of nuclear receptor co- action involves interaction with well-defined nuclear recep- regulators released upon receptor activation by the hormone; tors and regulation of gene transcription. However, rapid and (iv) involvement of a membrane-bound receptor, unre- effects of steroids have been reported which are incompatible lated to the classical nuclear receptor. In view of the plethoric with their classical long-term/slow effects. Although the con- physiological and pathophysiological effects of steroids, the cept of membrane-bound receptors for steroids which can discovery of such receptors and the characterization of their transduce their rapid effects has been proposed many years signaling pathways could have considerable importance, for ago, it is only recently that such proteins have been identified instance to envisage new therapeutic strategies. and characterized. In this review, we will discuss recent data In this review, we will discuss one example, namely the regarding the rapid action of progesterone mediated by newly hormone progesterone, and the recent and controversial iden- characterized membrane-bound receptors belonging to the tification of the so-called membrane progestin receptors progestin and adiponectin receptor family. (mPRs). The purpose of this paper is to contribute to the Keywords: membrane-bound receptors; non-genomic debate initiated by Fernandes et al. (9), who proposed to action; progesterone; steroid. share different points of view present in this field. Introduction Original observations and subsequent work by the Peter Thomas group The way in which steroids act is mainly described as a slow process involving gene transcription. This mechanism, During the late 1980s and early 1990s, the Peter Thomas known as the ‘‘genomic’’ pathway, was postulated more than group at the Marine Science Institute of the University of 60 years ago. During the past decades, this mechanism has Texas (Austin, TX, USA) identified a novel progestin (17,20- been investigated and particularly well described. It involves b,21-trihydroxy-4-pregnen-3-one or 20b-S) as the oocyte (i) the transport of steroid into the cell (either passively or maturation-inducing steroid in the teleost species (10, 11). using putative carriers); (ii) the binding of the hormone to The binding of this novel progestin was shown to occur at receptors trapped in the cytoplasm; (iii) the dimerization and the plasma membrane of oocytes with rapid dissociation and translocation of the ligand–receptor complex to the nucleus; association rates (12). To identify the putative receptors and (iv) the binding to specific nucleotide motifs and acti- involved in the binding of this steroid, this group developed vation of transcription (Figure 1). The receptors mediating an original and elegant multisteps procedure involving partial this ‘‘genomic’’ action belong to the steroid nuclear receptor protein purification steps to serve as an antigen to produce superfamily. monoclonal antibodies, a novel receptor–capture assay to The main characteristics of this process are therefore a isolate the antibodies recognizing the putative progestin delay of many hours between hormone treatment (release/ receptors, and the screening of a library expressing proteins administration?) and related biological effects, as well as the from sea trout ovaries with this selected antibody to isolate involvement of a nuclear receptor. However, steroids have the putative membrane progestin receptor cDNA. This meth- 2010/003 Article in press - uncorrected proof 42 A. Salhi et al. membrane domains, they exhibit an inverted topology when compared with G-protein-coupled receptors (GPCRs). Membrane progestin receptors function as GPCRs Although some members of the PAQR family are unrelated to GPCRs, observations reported by the Peter Thomas group indicate that mPRs display functional characteristics of this class of receptors. First of all, in contrast to adiponectin receptors and RKTG, the topology of mPR, as described by the Peter Thomas group, is that of a GPCR. In the original description (13, 14), the topology of mPR, with seven trans- membrane domains and an extracellular N-terminus part, was only extrapolated from in silico sequence analysis. Later, they showed that an antibody directed against the N-terminal part of sea trout mPRa recognized its target in non-permea- bilized cells, thereby establishing the extracellular localiza- Figure 1 Schematic representation of classical and non-classical tion of the N-terminal tail (21, 22). It should be underscored steroid actions. Steroids elicit classical, genomic effects (1) by binding to specific that the presence of seven transmembrane domains has never nuclear receptors (NRs) which then dimerize and are translocated been experimentally proven: neither for mPR nor for any into the nucleus. The steroid-bound receptor recruits different co- PAQR members. The main evidence of the Peter Thomas regulator forming a transcription complex and then binds to a hor- group suggesting that mPR are GPCRs was first obtained in mone response element (HRE) and triggers gene transcription. cells stably transfected with sea trout mPRa, where addition Steroids can also trigger rapid, non-classical effects in different of either progesterone or 20b-S induced a pertussis toxin- ways: disturbance of the lipid bilayer fluidity and modulation of sensitive decrease of cAMP, suggesting an inhibition of the membrane protein activity (2), binding to a pool of nuclear receptors adenylyl cyclases by a G0 or a Gi protein (13). Later, using present at the cell surface (3), release of nuclear receptor co-regu- native tissue, they demonstrated an interaction between 4 lators (Co-R) having their own activity ( ), and binding to mPRa or b with the inhibitory G protein in human myo- membrane-bound receptors (5). i metrial cells (23). More recently, Tubbs and Thomas (24, 25) showed that progestin-induced sperm hypermotility was od successfully led to the identification of a new class of related to mPRa stimulation followed by activation of a protein, called mPRs (13, 14). Research for orthologs stimulatory olfactory G protein (Golf) which induces an revealed that mPRs are well conserved in different species increase in intracellular cAMP. Thus, depending on tissues including mammals and particularly humans. In vertebrates, or cells, mPR could be associated with either an inhibitory there are at least three classes of receptors (a, b, and g) or a stimulatory G protein inducing opposite effects on which are differentially distributed and share 50–60% of cAMP cellular content. This observation is intriguing as homology at the protein level. The a receptor is mainly many tissues or cells expressed both Gi and Golf proteins. found in sex organs and to a lesser extent in the bladder, the The question is therefore how mPRs ‘‘choose’’ which G pro- adrenal glands, and the kidney. The b form is only neuronal tein they should associate with. The MAP kinase pathway is and the g form is found in epithelial tissues. It is noteworthy also triggered by activation of mPR proteins (13) but the link that the kidney is, so far, the only organ to express two with GPCR activity has not been established. forms, the a and the g receptors. A more detailed study regarding this non-reproductive organ has shown specific Subcellular localization of mPR localization of these isoforms along the nephron without any incidence of gender on their level of expression (15). Supporting this GPCR function, the Peter Thomas group According to their sequences, the three isoforms, mPRa, b, consistently observed the expression of mPR (irrespective of and g belong to a family of protein comprising adiponectin the isoform or the species) at the plasma membrane by using receptors 1 and 2, osmotin receptor, and RKTG (Raf Kinase different techniques (13, 21, 22). However, these authors also Trapping in Golgi also referred to as PAQR3) (16–18). This reported the co-localization