Estrogen receptor signaling through metabotropic glutamate receptors.

As the non-nuclear initiated effects of steroid hormone signaling have become more widely accepted, there has been a need to define the novel mechanisms of hormone receptor action that account for these outcomes. One mechanism that has emerged is the coupling of classical estrogen receptors (ERα and ERβ) with metabotropic glutamate receptors (mGluRs) to initiate G protein signaling cascades that ultimately influence neuronal physiology, structure, and behavior. Since its initial discovery in hippocampal neurons, evidence of ER/mGluR associations have been found throughout the nervous system, and the heterogeneity of possible receptor pairings afforded by multiple ER and mGluR subtypes appears to drive diverse molecular outcomes that can impact processes like cognition, motivation, movement, and pain. Recent evidence also suggests that the role of mGluRs in steroid hormone signaling may not be unique to ERs, but rather a conserved mechanism of membrane-initiated hormone receptor action.