Nongenomic effects of estrogen: why all the uncertainty?

It is clear that estradiol has profound, rapid effects on the conformation of the estrogen receptors (ERs), ERalpha and ERbeta, which mediate the transcriptional effects of estradiol. Estrogen can elicit many other rapid changes in cells including changes in ion fluxes across membranes and stimulation of kinases and phosphatases. The proteins which are the targets of these actions are the subject of intense investigation. One of the issues that have not been satisfactorily resolved is whether ERalpha or ERbeta can reside in the plasma membrane and participate in the rapid effects of estrogen. In the present commentary, we take a careful look at some of the published data in an attempt to understand why it is so difficult to obtain a definitive answer to this question.