Nongenomic actions of estrogen in the brain: Physiological significance and cellular mechanisms

Estrogen regulates neuroendocrine, reproductive, and behavioral functions of the brain by utilizing a number of diverse cellular mechanisms. In the classical genomic mechanism of steroids, estrogen induces relatively long-term actions on neurons by activating specific intracellular receptors that modulate transcription and protein synthesis. In addition, estrogen can also exert very rapid effects in the brain that cannot be attributed to genomic mechanisms. These nongenomic actions of estrogen influence a variety of neuronal properties, including electrical excitability, synaptic functioning, and morphological features, and are involved in many of the physiological functions and clinical effects of estrogen in the brain. Recently the specific cellular and molecular mechanisms underlying the nongenomic actions of estrogen have begun to be elucidated. Estrogen may utilize direct membrane mechanisms, such as activation of ligand-gated ion channels and G-protein-coupled second messenger systems and regulation of neurotransmitter transporters. Additionally the membrane and genomic actions of estrogen have the potential to interact, producing synergistic effects and dependence between the two types of mechanisms. The combination of nongenomic and genomic mechanisms endows estrogen with considerable diversity, range, and power in regulating neural function.