Review 569 Convergence of Multiple Mechanisms of Steroid Hormone Action Authors S. K. Mani 1 * , P. G. Mermelstein 2 * , M. J. Tetel 3 * , G. Anesetti 4 * Affi liations 1 Department of Molecular & Cellular Biology and Neuroscience, Baylor College of Medicine, Houston, TX, USA 2 Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA 3 Neuroscience Program, Wellesley College, Wellesley, MA, USA 4 Departamento de Hostologia y Embriologia, Facultad de Medicine, Universidad de la Republica, Montevideo, Uruguay Key words Abstract receptors can also be activated in a “ligand-inde- ● ▶ estrogen ▼ pendent” manner by other factors including neu- ● ▶ progesterone Steroid hormones modulate a wide array of rotransmitters. Recent studies indicate that rapid, ▶ ● signaling physiological processes including development, nonclassical steroid eff ects involve extranuclear ● ▶ cross-talk metabolism, and reproduction in various species. steroid receptors located at the membrane, which ● ▶ ovary ● ▶ brain It is generally believed that these biological eff ects interact with cytoplasmic kinase signaling mol- are predominantly mediated by their binding to ecules and G-proteins. The current review deals specifi c intracellular receptors resulting in con- with various mechanisms that function together formational change, dimerization, and recruit- in an integrated manner to promote hormone- ment of coregulators for transcription-dependent dependent actions on the central and sympathetic genomic actions (classical mechanism). In addi- nervous systems. tion, to their cognate ligands, intracellular steroid Abbreviations gene expression and function. Interestingly, not ▼ all the “classical” receptors are intranuclear and CBP CREB binding protein can be associated at the membrane. As described CRE CREB response element in this review, extranuclear ERs and PRs at the DAR Dopamine receptor (DAR) membrane or in the cytoplasm can interact with ER Estrogen receptor G proteins and signaling kinases, and other G received 13 . 12 . 2011 ERE Estrogen response element protein coupled receptors, to mediate rapid accepted 24 . 02 . 2012 mGluR Metabotropic glutamate receptor eff ects of the hormones. The rapid actions involv- PGMRC1 Progesterone membrane receptor ing cytoplasmic kinase signaling and/or extra- Bibliography nuclear steroid receptors can result in both DOI http://dx.doi.org/ component 1 10.1055/s-0032-1306343 PR Progestin receptor transcription-independent and transcription- Published online: PRE Progestin response element dependent actions. In addition, to their cognate March 27, 2012 SRCs Steroid receptor coactivators ligands, intranuclear steroid receptors (PRs) can Horm Metab Res 2012; also be activated in a “ligand-independent” man- 44: 569–576 ner by neurotransmitters (dopamine; DA). In this © Georg Thieme Verlag KG Introduction review, the distinct classical and nonclassical cel- Stuttgart · New York lular and molecular mechanisms of steroid hor- ISSN 0018-5043 ▼ Steroid hormones, estradiol (E2 ) and progester- mone action will be discussed with specifi c Correspondence one (P), regulate important physiological proc- reference to E2 and P eff ects in central and sym- S. K. Mani esses including development, diff erentiation, pathetic nervous systems ( ● ▶ Fig. 1 ) . Department of Molecular & metabolism, reproduction, learning, and mem- Cellular Biology ory in various species. The biological eff ects of E2 Baylor College of Medicine and P are primarily mediated by binding to their Mechanisms of Progesterone Action in One Baylor Plaza classical intranuclear receptors, estrogen (ERs) Brain Houston Texas 77030 and progestin receptors (PRs) that act as ligand- ▼ USA inducible transcription factors and interact with Ovarian steroid hormones, E2 and P regulate cel- Tel.: +1/713/798 6647 steroid receptor coregulators to modulate target lular functions in the central nervous system Fax: +1/713/790 1275 resulting in alterations in physiology and repro- [email protected] * All the authors contributed equally to this work. Mani SK et al. Mechanisms of Steroid Hormone Action … Horm Metab Res 2012; 44: 569–576 570 Review Fig. 1 Convergence of progesterone- and estradiol-mediated signaling in the nervous system. Through membrane, cytosolic, and intra- cellular receptors, these hormones aff ect surface membrane signaling, second messenger systems, and gene expression. Transcriptional co-factors are also intimately involved in the regulation of classical, steroid hormone-mediated as well as activity-dependent gene expression. ductive behavior. As in other steroid-sensitive tissues, the regu- female sexual receptive behavior has been demonstrated latory action of E2 on behavior is believed to involve the [ 18 , 19 ] . In addition, DA-initiated second messenger signaling activation of ERs, altering the expression of a number of genes, cascade was demonstrated to involve the activation of protein including PR gene. Progestins, including P, exert their physiolog- kinase A (PKA) and neuronal phosphoprotein, dopamine and ical eff ects primarily by binding to E2 -induced, intracellular PRs, cAMP regulated phosphoprotein-32 (DARPP-32) [ 20 ] . This sign- which function as transcriptional factors, regulating the expres- aling mechanism could potentially lead to the alterations in the sion of genes and genomic neural networks to initiate and/or phosphorylation dynamics and activation of PRs and/or its sustain physiological response [ 1 , 2 ] . PRs undergo signifi cant coregulators as discussed below. conformational change upon binding by P, leading to their While genomic eff ects characterized by a delayed onset have nuclear translocation, dimerization and DNA binding [ 3 ] . When traditionally been assumed to be the primary pathway for P bound to DNA, PRs interact with basal transcriptional machin- action in the brain, recent studies suggest the involvement of ery, assisted by coactivator molecules to initiate chromatin “nonclassical” mechanisms of progesterone action. These non- remodeling [ 4 – 6 ] . Phosphorylation of the coactivators also plays classical short-latency eff ects of progesterone widely aff ect cell a crucial role in the activation of steroid receptors [ 7 , 8 ] . The role functioning, through modulation of putative cell surface recep- of coactivators is discussed below. tors, ion channels and mechanisms coupled to cytoplasmic Spatial, temporal, and functional correlations indicate that E2 - second messenger signaling cascades, independent of gene tran- induced PRs function as transcriptional mediators and regulate scription [ 21 – 23 ] . In addition to P, several of its ring-A reduced transcription of target genes to aff ect reproductive behavior [ 2 ] . metabolites have been shown to facilitate lordosis response in The time course of activation and termination of reproductive ovariectomized, E2 -primed female rats via activation of MAPK behavior has also been shown to parallel E2 -induced increase pathway [ 17 ] . A number of laboratories have reported the and decline in PRs in the hypothalamus and the preoptic areas of involvement of at least 4 extranuclear kinase systems, PKA, PKC, the brain. A wide body of literature has identifi ed diff erent neu- CaMKII, and PKG in the rapid P eff ects in the VMH and POA of the roanatomical sites in the regulation of female sexual behavior by female rat [ 16 , 17 , 21 , 24 – 27 ] . Since the initiation of these non- steroid hormones [ 9 ] . Studies using PR antagonists, protein and classical eff ects occurs rapidly (in seconds or minutes) and is RNA synthesis inhibitors, antisense to oligonucleotides to PRm- triggered at the membrane surface, the classical model of RNA and PR mutant mice indicate a requirement for classical nuclear PR-mediation is inadequate to account for these eff ects. genomic mode of activation involving intracellular PRs in Recent evidence suggests the involvement of 2 types of novel P-mediated facilitation of reproductive behavior [ 10 – 15 ] . membrane proteins unrelated to classical PRs, progesterone Studies have also demonstrated that PRs can be activated by fac- membrane receptor component 1 (PGMRC1) and progesterone tors other than their cognate ligand, P (ligand-independent membrane receptors (mPRs), in P signaling in several reproduc- activation). Second messenger molecules, including 3′,5′-cyclic tive tissues and in the brain [ 28 , 29 ] . Inhibition of MAPK signaling adenosine monophosphate (cAMP), 3′,5′-cyclic guanosine mono- pathway results in reduction of P, dibutyryl-cAMP (db-cAMP)-, phosphate (cGMP), nitric oxide (NO), and neurotransmitter prostaglandin E 2 (PGE2 )-, or GnRH-facilitated female reproductive (dopamine, DA) can substitute for P in the facilitation of repro- behavior in rats [ 17 ] . These studies suggest that E2 and P actions ductive behavior [ 16 , 17 ] . Using PR antagonists, antisense oligo- in the brain could involve rapid activation of multiple signal nucleotides and null mutants for PRs, the critical requirement of transduction pathways that converge with classical genomic classical PRs as transcriptional mediators in the cross talk pathways. between P and DA-initiated pathways in the facilitation of Mani SK et al. Mechanisms of Steroid Hormone Action … Horm Metab Res 2012; 44: 569–576 Review 571 Nuclear Receptor Coactivators: The p160 Steroid expressed at high levels in the hypothalamus, cortex and hip- Receptor Coactivator Family pocampus of rodents [ 34 – 43 ] and birds [ 44 – 47 ] . Interestingly, in ▼ contrast with the other members of the SRC family,