ReviewEstrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways
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.
References (62)
- et al.
Sex differences in drug abuse
Front. Neuroendocrinol.
(2008) - et al.
Insulin-like growth factor I receptors and estrogen receptors colocalize in female rat brain
Neuroscience
(2000) - et al.
The many faces of CREB
Trends Neurosci.
(2005) - et al.
Estradiol inhibits ATP-induced intracellular calcium concentration increase in dorsal root ganglia neurons
Neuroscience
(2003) - et al.
Diversity of mechanisms involved in aromatase regulation and estrogen action in the brain
Biochim. Biophys. Acta
(2010) - et al.
Group I metabotropic glutamate receptor activation increases phosphorylation of cAMP response element-binding protein, Elk-1, and extracellular signal-regulated kinases in rat dorsal striatum
Brain Res. Mol. Brain Res.
(2001) - et al.
Mechanisms of ovarian steroid regulation of norepinephrine receptor-mediated signal transduction in the hypothalamus: implications for female reproductive physiology
Horm. Behav.
(2001) - et al.
Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons
Neuroscience
(2010) - et al.
Dopamine D1 receptor-induced signaling through TrkB receptors in striatal neurons
J. Biol. Chem.
(2008) Steroid hormones and excitability in the mammalian brain
Front. Neuroendocrinol.
(1997)
Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway
J. Biol. Chem.
Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle
Brain Res.
17Beta-estradiol inhibits high-voltage-activated calcium channel currents in rat sensory neurons via a non-genomic mechanism
Life Sci.
Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner
Neuroscience
Function and regulation of CREB family transcription factors in the nervous system
Neuron
Caveolin proteins and estrogen signaling in the brain
Mol. Cell. Endocrinol.
Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse
J. Biol. Chem.
VDAC and ERalpha interaction in caveolae from human cortex is altered in Alzheimer's disease
Mol. Cell. Neurosci.
Proximal events in signaling by plasma membrane estrogen receptors
J. Biol. Chem.
Studies of a plasma membrane steroid receptor in Xenopus oocytes using the synthetic progestin RU 486
J. Steroid Biochem.
Identification of a steroid receptor on the surface of Xenopus oocytes by photoaffinity labeling
J. Biol. Chem.
Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through Galpha(i)
J. Biol. Chem.
Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain
Endocrinology
Transplantation of testes. English translation by D.P. Quiring
Bull. Hist. Med.
Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons
J. Neurosci.
Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein
J. Neurosci.
A membrane estrogen receptor mediates intracellular calcium release in astrocytes
Endocrinology
Estradiol attenuates ATP-induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat DRG neurons
Estrogen receptor-alpha mediates estradiol attenuation of ATP-induced Ca2+ signaling in mouse dorsal root ganglion neurons
J. Neurosci. Res.
Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats
J. Neurosci.
17 beta-Estradiol potentiates kainate-induced currents via activation of the cAMP cascade
J. Neurosci.
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