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Review 569

Convergence of Multiple Mechanisms of 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 “-inde- ● ▶ ▼ pendent” manner by other factors including neu- ● ▶ Steroid 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 in various species. steroid receptors located at the membrane, which ● ▶ ● ▶ 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-. 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 -dependent dependent actions on the central and sympathetic genomic actions (classical mechanism). In addi- nervous systems. tion, to their cognate ligands, intracellular steroid

Abbreviations expression and function. Interestingly, not ▼ all the “classical” receptors are intranuclear and CBP CREB binding can be associated at the membrane. As described CRE CREB response element in this review, extranuclear ERs and PRs at the DAR (DAR) membrane or in the cytoplasm can interact with ER 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, (E 2 ) 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, E 2 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 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 , 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 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 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 E 2 (PGE 2)-, 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, SRC-3 is In the classic genomic mechanism of action discussed above, expressed sparsely in the hypothalamus [ 48 ] . In order for SRC-1 coregulators enhance (coactivators) or repress and SRC-2 to function with steroid receptors in brain, both the (corepressors) the steroid receptor transcriptional activity. Over coactivator and receptor must be expressed in the same cells. In 300 coactivators have been identifi ed, many of which have been support, SRC-1 and SRC-2 are expressed in the majority of estra- shown to function in physiology, behavior and human disease diol-induced PR cells in regions involved in metabolism and [ 30 ] . This review will focus on the role of the steroid receptor behavior, including the ventromedial hypothalamus (VMH), coactivator family in metabolism and brain and behavior. medial preoptic area and arcuate nucleus in rodents [ 35 , 49 ] . A The steroid receptor coactivator (SRC) family of p160 proteins variety of studies reveal that infl uence the expression of consists of SRC-1 (NcoA-1), SRC-2 (GRIP1/TIF2/NCoA-2), and these coactivators in brain [ 35 , 43 , 50 – 52 ] . Moreover, protein- SRC-3 (AIB1/TRAM-1/ACTR/RAC3/pCIP). This SRC family of coac- protein interactions studies reveal that SRC-1 and SRC-2 from tivators physically interacts with steroid receptors, including rodent brain physically associate with ER and PR in a receptor receptors for (AR), (ER), progestins (PR), and subtype- and brain region-specifi c manner [ 53 , 54 ] . (GR), in a ligand-dependent manner [ 31 ] . The A variety of studies using antisense to SRC-1 or SRC-2 mRNA C-terminus of the SRCs contains 2 activation domains (AD-1 and indicate that these coactivators are important for hormone AD-2), while the N-terminus contains a third activation domain dependent brain development and behavior. SRC-1 is critical for (AD-3) and a bHLH-PAS motif (basic helix loop helix-Per Arnt normal development of hormone-dependent sexual diff erentia- Sims), which is the most conserved domain within this family of tion of the brain and adult sexual behavior [ 40 ] . In the adult proteins. The activation domains interact with secondary coac- brain, SRC-1 and SRC-2 function in the VMH to modulate ER- tivators known as co-coactivators. These co-coactivators act as mediated transactivation of the behaviorally-relevant PR gene bridging molecules between the receptor and the general tran- [ 48 , 55 ] . In addition, SRC-1 functions in the VMH to infl uence scription machinery and modify chromatin within the promoter distinct ER- and PR-dependent aspects of female sexual behavior and enhancer regions by histone acetylation and methylation [ 56 ] . Interestingly, reduction of SRC-1 expression in this brain [31 ] . region by antisense altered PR function and reduced PR-depend- ent proceptivity (behavior by the female to solicit interaction by the male), but not PR-dependent receptivity [ 56 ] . These fi ndings The p160 SRC Family in Metabolism suggest that reduction of SRC-1 by antisense disrupted the activ- ▼ ity of PR signaling pathway(s) that infl uence proceptivity, while All 3 members of the p160 family of coactivators are involved in alternate PR signaling pathways, that regulate PR-dependent metabolic . SRC-1 is critical in maintaining energy receptivity, remained intact and functional. These coactivators, balance by regulating both energy intake and expenditure [ 32 ] . and others, have also been found to be essential in hormone In support, SRC-1 knockout mice have decreased energy expend- action in brain and behavior of birds [ 57 , 58 ] . iture and a reduced thermogenic capacity and thus, are prone to The p160 family of nuclear receptor coactivators has a critical obesity. One proposed mechanism of action for SRC-1 in metab- role in modulating steroid receptor action at the cellular level. In olism is through its interactions with PPARγ coactivator-1α the future, it will be important to determine the role of these (PGC-1α), an important regulator of mitochondrial biogenesis coactivators in nonclassical and membrane steroid signaling in and oxidative phosphorylation [ 32 ] . In contrast to SRC-1, SRC-2 brain discussed above and below, respectively. A better under- knockout mice are leaner than wild type mice and have an standing of how these important coactivators function in brain increase in adaptive thermogenesis [ 33 ] . It has been suggested is crucial to understanding the complex regulation of behavior that the absence of SRC-2 results in enhanced interaction and physiology by steroids. between SRC-1 and PGC-1α, which increases thermogenic activ- ity. Thus, it has been proposed that the ratio of SRC-1 and SRC-2 plays a role in maintaining the balance of energy expenditure Membrane Estrogen Receptors Activate and adipogenesis through controlling PGC-1α activity [ 33 ] . Metabotropic Glutamate Receptor Signaling SRC-3 knockouts have lower body fat content compared with ▼ wild-type mice [ 32 ] . SRC-3 mediates the transcriptional activity While we continue to appreciate the diversity of signaling of PPARγ2, which is important for adipocyte diff erentiation [ 33 ] . regarding the actions of nuclear ERα, ERβ and their associated In support, adipocyte diff erentiation and adipogenesis are proteins, estrogen receptors are also traffi cked to the surface impaired in mouse embryonic fi broblasts from cells isolated membrane, whereby they regulate various intracellular signal- from SRC-3 knockout mice or from 3T3-L1 adipocyte cells with ing pathways. Membrane-initiated estrogen action, both inside decreased levels of SRC-3 [ 33 ] . Taken together, these studies sug- and outside of the nervous system has been described for quite gest that the 3 members of the p160 SRC family play an impor- some time [ 59 , 60 ] . Yet, the identity of these membrane associ- tant role in energy homeostasis. ated receptors has for years remained controversial [ 61 ] . Several studies have suggested unique estrogen receptors acting at the membrane to initiate intracellular signaling [ 62 – 64 ] , while oth- The p160 SRC Family in Brain and Behavior ers have reported that these G-protein coupled receptors, local- ▼ ized to , are not activated by E2 and have A variety of recent studies indicate that 2 of the p160 SRC family no eff ect on intracellular signaling [ 65 ] . That said, in most sys- members, SRC-1 and SRC-2, are important for hormone action in tems, membrane-initiated steroid hormone action appears due brain and the regulation of behavior [ 34 ] . SRC-1 and SRC-2 are to the activation of a subpopulation of ERα and ERβ that have

Mani SK et al. Mechanisms of Steroid Hormone Action … Horm Metab Res 2012; 44: 569–576 572 Review

been modifi ed to traffi c and act at the neuronal surface [ 66 , 67 ] . to CREB phosphorylation were similarly segregated by expres- Determining how ERα and ERβ act at the membrane to aff ect sion of either caveolin-1 or caveolin-3. Surprisingly, however, intracellular signaling and how these estrogen receptors are the mGluRs responsible for membrane estrogen receptor signal- traffi cked to the membrane is critical to understanding estrogen ing in striatum were diff erent. In substitution of mGluR1a, ERα action in brain. was functionally coupled to mGluR5 in striatal neurons, whereas Recent studies have focused on estradiol-mediated phosphor- ERα and ERβ were paired with mGluR3 as opposed to in hippo- ylation (i. e., activation) of the CREB [ 68 , 69 ] . campus where these ERs activated mGluR2. These results are Phosphorylation of CREB is an important convergence point in interesting as each of these 4 mGluRs is expressed in both hip- , and is involved in various forms of neuronal plas- pocampus and striatum. These data suggest ERs may be promis- ticity, including learning and memory, drug addiction and noci- cuous regarding their coupling to various -coupled ception [ 70 ] , processes also under the infl uence of estrogens receptors. [ 61 ] . Work across multiple laboratories has indicated that acti- T r a ffi cking of ERα and ERβ to the membrane appears dependent vation of surface estrogen receptors leads to CREB phosphoryla- upon palmitoylation. Palmitoylation is the reversible addition of tion via stimulation of the MAPK/ERK signaling pathway the fatty acid palmitate to a protein. Palmitoylation aff ects the [ 71 – 73 ] . Furthermore, estrogen receptor knockout mice do not subcellular distribution and function of the modifi ed protein, exhibit estrogen-dependent CREB phosphorylation, indicating including promoting protein localization to membranes. Palmi- the dependence upon ERα and ERβ [ 74 ] . toylation occurs most commonly on residues, and is To elucidate the signaling mechanisms by which estradiol aff ects mediated by a family of proteins called palmitoyl acyltrans- CREB phosphorylation, initial studies utilized primary cultures ferases (PATs). There are 23 unique PATs, each derived from a from rat hippocampus [ 75 ] . Estradiol stimulation of membrane separate gene (DHHC 1–9, 11–24). Previous work in cell lines ERα was found to initiate mGluR1 signaling. These actions of demonstrated ERα incorporates radiolabeled palmitate [ 82 ] . estradiol/ERα on mGluR1 were independent of glutamate and Substitution of the palmitoyl cysteine residue with alanine only occurred in cultures generated from female rats. ERα acti- blocks both radiolabeling of ERα as well as membrane-initiated vation of mGluR1 signaling led to CREB phosphorylation via Gq- ERα responsiveness [ 82 – 84 ] . In neurons, recent fi ndings indicate mediated stimulation of phospholipase C (PLC), protein kinase C that palmitoylation of ERα and ERβ is essential for membrane ER (PKC) and trisphosphate (IP3). Interestingly, this was not localization, association with caveolin proteins, and activation the only membrane-initiated signaling pathway sensitive to mGluR signaling [ 81 ] . estradiol. In these same neurons, estradiol-mediated activation Using a simplifi ed model system (i. e., cultured neurons) it has of ERα or ERβ would lead to activation of mGluR2. Activation of been possible to identify this potential mechanism of estrogen these Gi/o G protein-coupled receptors by estradiol would lead action in brain. Work from a number of labs has expanded the to an attenuation of L-type calcium channel-mediated CREB importance of these studies to the whole animal, to additional phosphorylation. This was consistent, as well as provided a brain regions, and correspondingly, to additional behaviors. The mechanism, regarding previous fi ndings of estradiol inhibition fi rst report demonstrating the importance of ER/mGluR signal- of L-type calcium channels [ 76 ] . ing related to membrane estrogen action on the regulation of rat While CREB phosphorylation is only one of many downstream lordosis [ 85 ] . Specifi cally, within the arcuate nucleus, ERα acti- targets of mGluR activation, it was somewhat surprising to vation of mGluR1 signaling is essential for full sexual receptivity. observe estradiol regulating opposing processes within the In a separate study, regulation of the estrous cycle by membrane same cell. That is, at least, if gonadal estrogens are the principal ERs is dependent on ERα activation of mGluR1 in hypothalamic activators of ER/mGluR signaling. However, recent work has pro- astrocytes [ 86 ] . Examining dorsal root ganglion neurons in a vided several clues that brain-derived estrogen (i. e., neuroestro- model of nociception, estrogen receptor activation of mGluR2/3 gen) may be the critical mediator of rapid estrogen signaling attenuates ATP-induced increases in intracellular calcium via [77 ] . Specifi cally, not only does estradiol directly aff ect the elec- inhibition of L-type calcium channels [ 87 ] . Additionally, estro- trochemical state of the cell, but also synthesis of estradiol from gen-induced masculinization of the medial preoptic area is aromatase localized to presynaptic boutons suggests estradiol dependent upon mGluR [ 88 ] . ER/mGluR signaling has also been may act as a neurotransmitter [ 78 – 81 ] . A universal characteris- demonstrated to aff ect spinogenesis [ 89 ] , and recent fi ndings tic of neurotransmission is that the ligand release point is proxi- indicate ER/mGluR coupling is responsible for estrogen-induced mal to the location of the cognate receptor. Thus, if ER/mGluR release of endocannabinoids in hippocampal neurons [ 90 ] and signaling acts as similar to a traditional neurotransmitter sys- the potentiation of dopamine release in the female striatum fol- tem, these signaling proteins must also be spatially restricted. In lowing the administration of a psychostimulant [ 91 ] . Over the fact, caveolin-1 expression was found to be essential for the next several years, it is likely that other membrane actions of functional coupling of ERα with mGluR1a, whereas, caveolin-3 estradiol will also be shown dependent upon activation of is necessary for ERα and ERβ activation of mGluR2 [ 68 ] . Hence, mGluRs. the spatial segregation of diff erent ER/mGluR signaling path- ways can allow for independent activation and inhibition of CREB phosphorylation. Estrogens and Sympathetic Innervation in Female Because membrane estrogen receptor signaling is widespread Reproductive System both inside and outside of the nervous system, it was deter- ▼ mined whether ERs were coupled to mGluR signaling in other In addition to the variety of mechanisms by which estrogens act brain regions. Similar to previous results in hippocampal cul- in brain to regulate female reproductive behavior discussed tures, bidirectional eff ects of estradiol on CREB phosphoryla- above, estradiol infl uences the function of sympathetic neurons tion, dependent on ER/mGluR signaling, were found in striatal associated with reproductive organs in a variety of ways. The neurons [ 68 ] . Moreover, opposing ER/mGluR processes related sympathetic system includes preganglionic neurons located in

Mani SK et al. Mechanisms of Steroid Hormone Action … Horm Metab Res 2012; 44: 569–576 Review 573

the intermediolateral column at the thoracic and lumbar levels gens during the rodent estrous cycle and pregnancy induce of the spinal cord, which synapse with postganglionic neurons changes in sympathetic nerve density, including a progressive located in sympathetic ganglia. Axonal projections of these neu- loss of sympathetic activity at late gestation [ 110 ] . In the ovary, rons are dependent on several guidance and survival signals estradiol treatment induces an augmented synthesis of NGF provided by target organs [ 92 ] . These neurons display immuno- associated with an increase in content that can reactivity for one or both of the ER subtypes [ 93 , 94 ] . While induce long-lasting eff ects on the sympathetic innervation of almost all sympathetic neurons express ERβ, only about a third the . These changes alter ovarian morphology and func- of these neurons express ERα [ 95 ] . In some instances sympa- tion; induce the development and maintenance of cystic folli- thetic neurons in lumbar paravertebral and prevertebral ganglia cles, and cause anovulation and alterations in estrous cyclicity display cytoplasmic ER-immunoreactivity [ 94 , 96 ] . This cyto- [ 111 , 112 ] . Similar changes are found in ovaries from women plasmic distribution has been attributed to the presence of ERα with polycystic ovary syndrome (PCOS), a common cause of isoforms lacking nuclear localization signals and thus unable to infertility during reproductive age [ 113 ] . In animal models of respond to estrogens [ 97 ] . The membrane ER, GPR30, may also PCOS, the eff ects induced by estradiol exposure can be partially mediate signaling. Immunohistochemical and in situ hybridiza- reversed by surgical sympathectomy [ 111 , 114 ] . A potential con- tion studies reveal expression of GPR30 in some regions of brain, tribution of the sympathetic system to PCOS has been suggested spinal cord and peripheral tissues [ 98 ] . However, it is not known given that polycystic ovaries show an increase in the number of if GPR30 are expressed or function in postganglionic sympa- sympathetic fi bers [ 115 ] and ovarian wedge resection or laparo- thetic neurons. scopic laser cauterization are eff ective in increasing the ovula- Sympathetic fi bers that innervate the ovary originate mainly tory response in women with PCOS [ 116 ] . These fi ndings raise from the complex celiac-mesenteric ganglia. Ovarian innerva- the possibility that sympathetic input may play a role in the tion is associated with growing follicles, interstitial tissue and development and maintenance of polycystic ovaries in PCOS ovarian vasculature [ 99 ] . Two of the major neurotransmitters women. contained in the ovarian nerves, norepinephrine (NE) and In summary, estradiol can regulate several aspects of sympa- vasoactive intestinal polypeptide (VIP), are considered modula- thetic neuronal function through a variety of mechanisms. Neu- tors of steroid production [ 100 ] . Several studies show the rele- ronal target tissues can be infl uenced by these estradiol-induced vance of neural sympathetic infl uence on follicular assembly, changes. While estrogens can have direct eff ects by acting acquisition of responsiveness to gonadotropins and regulation of through neuronal ERs, they can also act indirectly to elicit ovarian steroidogenesis [ 101 , 102 ] . changes in production of survival signals in target organs that Estradiol produced by growing ovarian follicles has signifi cant aff ect the function of subpopulations of neurons. Knowledge of paracrine and autocrine eff ects that can infl uence gonadal phys- the basic mechanisms of this crosstalk is essential in under- iology. Estrogen action is mediated by ERs in follicular structures standing the pathophysiological aspects involved in the devel- and the stroma of the ovary. ERβ expression in granulosa cells is opment and maintenance of complex hormone-dependent essential for cell diff erentiation and function [ 103 ] , while ERα disorders aff ecting human health. expressed in thecal and interstitial cells are crucial for steroido- genesis [ 104 ] . Some eff ects of estradiol on sympathetic innervation are medi- Conclusions ated by changes in the expression of neurotrophins, including ▼ nerve (NGF), a signaling molecule involved in sur- The research outlined in this review (e. g., mechanisms of PR vival and diff erentiation of sympathetic and sensorial neurons. activation, transcriptional coactivators, membrane/nuclear sig- In the rat ovary, neurotrophins are produced in cells of the fol- naling, neuronal feedback to the reproductive organs) refl ects licular wall and are responsible for the development of ovarian how far the fi eld of neuroendocrinology has progressed over the sympathetic innervation [ 105 ] . The actions of these neuro- last several years. Clearly, steroid hormone action in the nervous trophins are mediated by 2 receptors: 1) the 75 kDa low-affi nity system is not a simple on/off activational relay. Based upon the neurotrophin receptor (p75NGFR), which displays rapid associa- role these hormones play in a diversity of physiological tion and dissociation with most members of the neurotrophin responses, this is not surprising. Over the next several years, we family and 2) a high-affi nity tyrosine kinase (TrkA) receptor, can expect basic science to provide additional breakthroughs as which binds NGF more specifi cally but with slow kinetics [ 106 ] . these fi ndings are integrated into a comprehensive study of Estrogen-responsive elements have been identifi ed in many of endocrine and neuroendocrine responsiveness. This work will the genes that code for neurotrophins or their receptors [ 107 ] . ultimately impact the treatment of various hormonal and meta- NGF production induced by estradiol exposure may diff er bolic disorders. depending on the tissue being analyzed [ 108 ] . In addition, vari- ations in estrogen levels alter neurotrophin receptor expression in sympathetic neurons, thus modulating neurotrophin respon- Acknowledgements siveness. This neurotrophin response varies with the neuronal ▼ population analyzed, the doses administered and the physiolog- The studies contributed to this work were supported by Public ical status of animals (e. g., prepubertal, adult cyclic, or adult Health Service grants from National Institutes of Health HD pregnant rat) [ 94 , 109 ] . 062512 (SKM), National Institutes of Health R01 DK61935 (MJT), Mounting evidence indicates that changes in estrogen signaling National Institute of Health NS 041302 and core funding NS and adrenergic innervation can induce alterations in sympa- 062125 (PGM), and grants from National Science Foundation thetic tone. The most dramatic modifi cations are seen in the IBN 0080818 (MJT). myometrial layer of uterus, where variations in levels of estro-

Mani SK et al. Mechanisms of Steroid Hormone Action … Horm Metab Res 2012; 44: 569–576 574 Review

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