Review
Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways

https://doi.org/10.1016/j.jchemneu.2011.02.002Get rights and content

Abstract

Estradiol and other steroid hormones modulate the nervous system and behavior on both acute and long-term time scales. Though estradiol was originally characterized as a regulator of gene expression through the action of nuclear estrogen receptors (ERs) that directly bind DNA, research over the past thirty years has firmly established that estradiol can bind to extra-nuclear ERs associated with the cellular membrane, producing changes in neurons through stimulation of various intracellular signaling pathways. Several studies have determined that the classical ERs, ERα and ERβ, mediate some of these fast-acting signaling pathways through activation of G proteins. Since ERα and ERβ are not G protein-coupled receptors, the mechanisms by which ERs can stimulate signal transduction pathways are a focus of recent research. Here we discuss recent studies illustrating one mechanism by which ERα and ERβ initiate these pathways: through direct association with metabotropic glutamate receptors (mGluRs). Estradiol binding to these membrane-localized estrogen receptors results in mGluR signaling independent of glutamate. ERs are organized with mGluRs into functional signaling microdomains via caveolin proteins. The pairing of ERs to specific mGluRs via caveolins is region specific, with ERs being linked to different mGluRs in hippocampal, striatal, and other neurons. It is becoming clear that ER signaling through mGluRs is one important mechanism by which estrogens can modulate neuron and glial physiology, ultimately impacting various aspects of nervous system function.

Highlights

► The classical estrogen receptors ERα and ERβ stimulate metabotropic glutamate receptors to initiate intracellular signaling cascades. ► Different ERs and mGluRs are organized into functional signaling microdomains via caveolins. ► There are brain region differences regarding the organization of ERs, mGluRs and caveolin proteins.

Introduction

Steroid sex hormone actions on brain and behavior have been studied for over 160 years, beginning with Arnold A. Berthold (1803–1861) and his studies with intact and castrated roosters (Berthold, 1944). The last 65 years in particular have seen an explosion in the number of studies focusing on the effects of gonadal hormones on brain function and behavior, heavily influenced by the work of Frank Beach (1911–1988) and his landmark book Hormones and Behavior, first published in 1948. It is now well established that steroid sex hormones influence the nervous system and behavior permanently, temporarily, slowly and rapidly, via changes in gene expression and other cellular processes. Steroid sex hormones have been shown to modulate brain anatomy and physiology, affect multiple behaviors, including sexual development and reproduction, and more recently, various processes outside of reproduction, including learning and memory, nociception, motor control, drug use and cognition.

The goal of this review is to focus on recent findings regarding the conversion of the intracellular estrogen receptors, ERα and ERβ into membrane associated signaling proteins, whereby they interact with metabotropic glutamate receptors (mGluRs) to rapidly trigger intracellular signaling pathways. In the course of reviewing this body of work, we will first provide background on the classical actions of ERs, and then follow with a brief discussion of the mechanisms of acute estrogen action with ERs working at the membrane surface. We will then discuss how ERs link to mGluRs to initiate signaling cascades, and how ERs and mGluRs are organized into functional signaling microdomains via caveolins. Finally, we will examine how ERs, mGluRs and caveolins are differentially organized by brain region.

Section snippets

Classical actions of estrogen receptors

The classical action of estrogens, including 17β-estradiol, is stimulating ERs to directly induce changes in gene expression and protein synthesis. Across many brain regions and animals, many ER-mediated effects are dependent on translation of mRNA into protein. Indeed, both types of classically described ERs, ERα and ERβ, can act as ligand-regulated transcription factors. ERα and ERβ are primarily localized in the nucleus, where after activation they can modulate gene expression by binding to

Acute actions of estrogen receptors

This fairly straightforward and simple model of estrogen action is useful for explaining many estrogen actions, but has proven to be incomplete. Alongside the growing evidence that ERs act to modulate gene expression on relatively slow time scales, reports of estrogen action incompatible with this model were slowly being added to the literature. These reports generally fell within three categories: rapid actions of estrogen on both reproductive and non-reproductive behavior, actions that seemed

ERs interacts with mGluRs to activate intracellular signaling pathways

One of the questions generated by this research is how classical ERs trigger signal transduction pathways, given that they are not G protein-coupled receptors and are localized to the cellular membrane. Ours and other laboratories have found that ERα and ERβ can stimulate metabotropic glutamate receptors (mGluRs) to initiate intracellular signaling cascades. mGluRs are a family of G-protein coupled receptors that trigger G-protein activation after being bound by glutamate. There are at least

ER association with particular mGluRs is brain region specific

The general finding that rapid ERα and ERβ effects of CREB phosphorylation are mediated through mGluRs, but not necessarily through the same mGluRs, has also been extended to neurons from other brain regions. For our next set of experiments we focused on striatal neurons, as the rapid estrogen actions reported in this brain region are also consistent with mGluR signaling (Becker and Hu, 2008). As with hippocampal neurons, we found that activation of ERα triggers CREB phosphorylation, and that

Caveolins organize ERs and mGluRs into functional microdomains

The preceding paragraphs describe how ERs link to different mGluRs both within the same neuron, and between different brain regions. Several different mechanisms are known to functionally organize signaling pathways such as this, with one prime candidate being caveolins (Stern and Mermelstein, 2010). Caveolin proteins are situated in the membrane and create functional microdomains of signaling proteins. They are well known to interact with both steroid sex hormone receptors and mGluRs (Patel et

Physiological impact of ERs signaling through mGluRs

Functional linkage of ERs with different mGluRs creates the potential for a vast diversity of estrogen-sensitive signaling pathways (Fig. 1B). Though activation of group I receptors stimulates CREB phosphorylation via the same pathway as estradiol (Choe and Wang, 2001, Warwick et al., 2005), mGluRs do much more to affect neuron physiology than just phosphorylate CREB (Niswender and Conn, 2010). With the added complexity of caveolin-created functional microdomains, the ER-mGluR relationship may

Conclusions

Here we have discussed recent research into the mechanisms underlying rapid estrogen action in neurons, emphasizing that membrane-associated ERα and ERβ can stimulate mGluRs to initiate signal transduction pathways. Furthermore, which mGluRs are activated are signal transduction pathway and brain region specific, and that functional signaling domains created by caveolin proteins explain some of these effects. These data serve as a potential mechanism by which many rapid estrogen effects could

Acknowledgments

The authors acknowledge support from NIH grants NS041302 (PGM), T32 DA07234 (training grant supporting JM), and F32 DA030828 (JM). We thank the participants in the Workshop for Steroid Hormones and Brain Function for stimulating discussion.

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