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

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.

► 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.