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

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 (ER) that directly bind DNA to regulate gene expression, research over the past thirty years has firmly established that estradiol can initiate signaling pathways via 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.

Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity

“…Although G␣ i ␤␥ mediates the ER␣-induced neuroprotective effect ), a G q -mediated signaling has also been linked to membrane ER␣ activation in astrocytes (Chaban et al, 2004). Our data, however, support the hypothesis that membrane ERs are not themselves G protein-coupled receptors but rather use mGlu1 receptor to signal, as previously suggested Meitzen and Mermelstein, 2011). MAPK signaling is known to participate in the neuroprotective effect of estrogen.…”

Membrane-Initiated Estradiol Signaling Induces Spinogenesis Required for Female Sexual Receptivity

“…This interaction between ER␣ and mGluR1a has been shown to be important for the control of both female sexual receptivity and the release of neuroprogesterone from astrocytes in the hypothalamus (for review, see Micevych and Mermelstein, 2008;Micevych et al, 2009). In fact, recent work has shown that ERs may be able to interact with several different kinds of mGluRs in brain-region-specific patterns to activate many G-protein-coupled signaling cascades (Meitzen and Mermelstein, 2011).…”

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…Moreover, dorsal hippocampal infusion of BSA-E 2 in adult ovariectomized mice induces a similar ERK-dependent enhancement of object recognition memory consolidation to that observed after dorsal hippocampal infusion of free E 2 (Fernandez et al 2008), suggesting that membrane ERs mediate the memory-enhancing effect of E 2 by activating ERK signaling. Data such as these have led to a general acceptance that a membrane-associated ER facilitates the rapid nonclassical effects of E 2 (e.g., Micevych and Dominguez 2009) and have prompted some investigators to suggest that BSA-E 2 binds to ERa and ERb localized within the membrane (Meitzen and Mermelstein 2011). Although one provocative report indicates that ERa in the hypothalamus has an extracellular domain and can be internalized by E 2 and mGluR1a ligands (Bondar et al 2009), it is not yet widely accepted that ERa is an integral membrane protein.…”