Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways - PubMed (original) (raw)

Review

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

John Meitzen et al. J Chem Neuroanat. 2011 Dec.

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.

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Figures

Figure 1

ER activation of mGluRs is organized via caveolins into brain region specific functional microdomains. A. Schematic of proposed estradiol/ER/mGluR signaling microdomains as organized by caveolin proteins in hippocampal neurons. Caveolin 1 organizes ERα to mGluR1a to activate the MEK pathway which induces CREB phosphorylation. Caveolin 3 organizes ERα to mGluR2 which activates PKA/CaM signaling to attenuate CREB phosphorylation. Abbreviations: ER, estrogen receptor; AC, adenylyl cyclase; PKA, protein kinase A; CaM, Calmodulin; CaMKIV, calmodulin-dependent protein kinase IV; PLC, phospholipase C; MEK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; RAF, rapidly accelerated fibrosarcoma kinase; RSK, p90 ribosomal protein S6 kinase; CREB, cyclic-AMP response element binding protein. B. Summary depicting how ERs link to different mGluRs depending on brain region. Question marks indicate as yet undetermined caveolins or mGluRs.

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Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways - PubMed (original) (raw)