Nongenomic Actions Of Estrogens And Variants On The Genomic Actions

The puzzle that estradiol affects hippocampal pyramidal neurons that do not appear to have intracellular estrogen receptors might be explainable if there were cell-surface estrogen receptors. Rapid estrogen effects on CA1 pyramidal neurons of the hippocampus have been described in electrophysiological studies on slices, and these appear to involve non-NMDA excitatory amino acid receptors (110,111), that are very likely to be a-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptors (112). One approach to rule in or out of nongenomic actions of estradiol would be to study mice lacking intracellular estrogen receptors (113); however, these mice do have some estrogen binding, although they lack a number of known genomic estradiol actions in the reproductive tract (113). Another approach to discriminate between classical estrogen receptor and membrane estrogen receptor is to use anti-estrogens that bind to the intracellular estrogen receptor, but that do not block the rapid membrane effects (114).

Anti-estrogens also have another useā€”namely, to discriminate between the response elements that the estrogen receptor uses to activate transcription. Nonsteroidal anti-estrogens bind to estrogen receptors and activate transcription via AP-1 response elements (115), while blocking transcriptional activation through the classical estrogen response element (ERE) and not producing any agonist effect via this pathway (116).

A final note on the question of genomic estrogen receptor is that some cells may express a low level of estrogen receptors that is undetectable by conventional means. Such a possibility has been investigated using a transgenic animal with an estrogen receptor promoter attached to a reporter gene (117). Although the distribution of the estrogen receptor-directed reporter gene generally agrees with the estrogen receptor itself, an overall low level of expression in brain tissue that did not manifest itself as discrete labeled cells keeps open the possibility that a low level of expression of estrogen receptors may exist in ubiquitous cell types, including glia (117).

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