The further redefining of steroid-mediated signaling.

Abstract

The classical paradigm of steroid hormone action is that intracellular receptors bind to specific steroids to modulate gene expression within the nuclei of target cells. However, increasing evidence now suggests that many important steroid-induced signaling events are triggered independent of transcription. Examples of “nongenomic” biological responses to steroids include estrogen-induced proliferation of breast cell lines (1), estrogen-mediated dilation of blood vessels (2, 3), and progesterone-induced activation of the acrosomal reaction in sperm (4). The signaling mechanisms responsible for these biological responses are diverse, such as activation of signaling molecules Src, extracellular signal-regulated kinase (ERK), endothelial nitric-oxide synthase (eNOS), and Akt, as well as rapid alterations in intracellular calcium and cAMP levels (5). Experiments designed to identify steroid receptors that may modulate these nongenomic processes have produced several candidates, including classical steroid receptors located in the membrane (1, 3, 6), traditional G protein-coupled receptors (GPCRs) (7, 8), and novel membrane-associated steroid binding proteins (9). In most cases, however, the true physiologic importance of these receptors has yet to be proven. Two articles by Zhu and colleagues (10, 11) in this issue of PNAS provide new and provocative insight toward identifying potentially physiologically relevant steroid receptors capable of mediating nongenomic signaling, describing a novel family of high-affinity membrane steroid receptors with structure and signaling similar to GPCRs.