ReviewNon-genomic actions of estrogens and their interaction with genomic actions in the brain
Introduction
Estrogens are important endocrine effectors of reproduction [139], [135], [86]. They are ligands for either ERα or ERβ; these receptors are isoforms that belong to the nuclear receptor superfamily. In common with other members of the nuclear receptor superfamily, they possess a modular domain structure with different modules possessing different functions such as DNA binding, dimerization, ligand-binding and transcriptional activation [120], [130], [85], [51], [127]. They also play an important and sometimes permissive role in liver and cardiovascular physiology, neuronal growth and differentiation, neuroprotection, cognition and in the regulation of mood [26], [28], [99], [105]. The molecular mechanisms by which estrogens change the response of target tissues can be broadly divided into two categories: (a) genomic actions and (b) non-genomic actions. In this review, we focus first on the non-genomic actions of estrogens that are known to be important in the central nervous system (CNS) and second, on the interaction between non-genomic and genomic actions of estrogen with respect to transcription.
Section snippets
The genomic mode of estrogen action
Genomic actions are those wherein the binding of estrogens to either of the ER isoforms results in regulation of transcription of genes ([127] and references therein). In the absence of estrogens, the ER in various target tissues is associated with heat-shock proteins in a transcriptionally inactive state [49]. However, binding of 17β-estradiol, the natural endogenous ligand, or a similar agonist molecule to the ER induces a conformational change in the ER. This promotes ER homodimerization and
Membrane-initiated hormone actions potentiate their transcriptional actions
The hypothesis that rapid signaling cascades initiated at the membrane by estrogens can lead to changes in transcription from ERE-containing genes is inspired by data that suggests that reproductive behavior in female rodents is dependent both on gene expression as well as kinase activation and changes in neuronal excitability by estrogens. Hence, this is a good physiological scenario in which one can study if rapid effects such as kinase activation and neuronal excitability regulate gene
Models of signal transduction cascades in response to estrogen in neurons and non-neuronal cell types
The experimental strategy using inhibitors and activators to different kinase cascades and calcium channels resulted in several kinases being implicated in E2-BSA-mediated transcriptional potentiation. We attempted to construct models of signaling hierarchies that could serve as hypotheses as to the sequence of events that take place once E2-BSA is at the membrane in neuroblastoma cells [187], These models were constructed taking into account both, the signaling cascades elucidated by us, and
Coupling of the membrane-initiated actions of estrogen to transcription involves protein–protein interactions, protein translocation and protein phosphorylation
In this review, we have established, that rapid membrane-initiated actions of estrogens have relevance to the final response of the tissue to estrogen and that in most of these cases, genomic actions of estrogens involving transcription from genes also impacts the final phenotype. Our study using the consensus ERE provides direct evidence that these two pathways can interact and other studies, notably from the Dorsa and Levin Laboratories [193], [133], have shown that rapid signaling can
The membrane estrogen receptor could be a novel protein in some cell types
The elucidation of the membrane estrogen receptor (mER) has generated enormous interest and effort [35], [53], [191], [190], [192] since knowledge of a mER can lead to a more complete dissection of membrane-initiated signal transduction pathways activated by estrogens [189]. Any protein that is a candidate mER should bind 17β-estradiol with specificity and saturability and be present at the plasma membrane of the cell to initiate rapid membrane-initiated action. Both localization to the
Summary and future directions
Data from other laboratories and ours suggest that both kinases and calcium flux appear to be important in E2-BSA-mediated actions on transcription in neurons. Several different, parallel pathways can couple signal transduction cascades to transcription in the nucleus. In this review, we have discussed the binding of cognate ligands to membrane receptors such as the mER or a novel protein which acts as the mER which activates kinase cascades which in turn, can facilitate transcription from
Acknowledgments
We thank Dr. Lee Ming Kow (Laboratory of Neurobiology and Behavior, The Rockefeller University), Dr. V.P. Nair and Dr. Alexander Punnoose (Department of Physics, CCNY, CUNY, New York) for helpful discussions during the course of this work.
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