Steering estrogen signals from the plasma membrane to the nucleus: Two sides of the coin

Estrogen mediate its biological effects through its association with estrogen receptors (ERs). They also regulate the expression of a variety of genes involved in distinct physiological processes, including development, metabolism, and reproduction. In addition, emerging data suggest that the estrogen-estrogen receptor complex can also function as a cytoplasmic signaling molecule and may influence processes such as cardiovascular protection, bone preservation, neuroprotection, and proliferation of various cell types. Such extranuclear or nongenomic signaling pathways are rapid and supposedly independent of transcription. A recent exciting finding was that G-coupled membrane protein receptor, GPR30, an alternative to the classical ERs, is also involved in the rapid signaling of estrogen through its direct association with estrogen. These new findings combined with the recent advances in the cytoplasmic functions of proline, glutamic acid, luecine rich protein 1 (PELP1), and metastatic tumor antigen 1 short form (MTA1s) have opened a new spectrum and raised several new concerns in the field of estrogen biology and put the attention to unveil many unknown mechanistic actions of estrogen in cellular physiology. In this review, we briefly summarize what is currently known of the cellular mechanisms and physiology of estrogen's nongenomic actions in various cellular systems used by ERs.