Membrane estrogen receptors acting through metabotropic glutamate receptors: An emerging mechanism of estrogen action in brain

It has been over 60years since the first studies have been published describing the effects of steroid hormones on brain function. For over 30years, estrogen has been presumed to directly affect gene expression and protein synthesis through a specific receptor. More than 20years ago, the first estrogen receptor was cloned and identified as a transcription factor. Yet, throughout their course of study, estrogens have also been observed to affect nervous system function via mechanisms independent of intracellular receptor regulation of gene expression. Up until recently, the membrane estrogen receptors responsible for these rapid actions have remained elusive. Recent studies have demonstrated that a large number of these rapid, membrane-initiated actions of estradiol are due to surface expression of classical estrogen receptors. This review focuses on the importance of membrane estrogen receptor interactions with metabotropic glutamate receptors for understanding rapid estradiol signaling mechanisms and downstream effectors, as well as their significance in a variety of physiological processes.