Estrogen: nontranscriptional signaling pathway

The long-term, genomic actions of estrogen and other steroid hormones are now relatively well understood. In this process, steroids bind to a cytoplasmic/nuclear receptor and the hormone receptor complex that, in turn, binds to DNA and triggers RNA-dependent protein synthesis. This process produces a response over time periods of several minutes to hours to days. Estrogen also exerts a variety of short-term effects (observed in milliseconds to minutes) on target organs that are not compatible with the classical genomic mechanism. These short-term, nontranscriptional actions are thought to be neuromodulatory in nature and critical for cell-cell communication. This chapter discusses current evidence for nontranscriptional effects of estrogen, with major emphasis on electrophysiological results demonstrating rapid, estrogen-induced changes in neuronal excitability. The mechanisms for nontranscriptional estrogen effects are also considered. These mechanisms include nonspecific influences on the lipid bilayer, specific binding to novel membrane receptors, direct modulation of neurotransmitter-ion channel complexes, and direct activation of second messenger systems. Particular attention will be focused on studies from our laboratory investigating mechanisms of estrogenic potentiation of kainate-induced currents in hippocampal neurons. Finally, the physiological relevance of short-term estrogenic actions will be addressed.