Cellular and molecular basis for acute nongenomically mediated actions of SERMs

Abstract

Compelling evidence accumulated over the past three decades have demonstratedthat, besides their ability to antagonize estrogen binding to their intracellularspecific estrogen receptors (ER), selective estrogen receptor modulators(SERMs) can affect a number of biochemical processes in eukaryoticcells. Experimental data from in vivo and in vitro studies have revealed thatSERMs and estrogens are surprisingly pleiotropic molecules affecting moleculartargets in both estrogen receptor positive (ER+) and negative (ER-) cells.Such "alternative" actions of SERMs and estrogens are typically independentof canonical ERs and do not involve transcriptional or translational events,thereby mediated nongenomically, and usually initiated (and accomplished)within seconds to minutes after presentation of the molecule (Falkestein et al.2000;Nadal el al. 2001). The spectrumof SERM-induced acute actions includesa wide set of molecular targets, frommodulation of ion channels and signalingmolecules to alteration of membrane fluidity. In the following sections we reviewdata from different laboratories, including ours, in the context of cellularand molecular evidences for acute nongenomic effects of SERMs observed atpharmacological circulating concentrations. Special emphasis will be placedon actions that might underlie clinically relevant beneficial effects as well asundesirable side effects. © Springer-Verlag Berlin Heidelberg 2006.