The further redefining of steroid-mediated signaling.

T he 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 steroidinduced signaling events are triggered independent of transcription. Examples of ‘‘nongenomic’’ biological responses to steroids include estrogen-induced proliferation of breast cell lines (1), estrogenmediated 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 nitricoxide 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 membraneassociated 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 highaffinity membrane steroid receptors with structure and signaling similar to GPCRs. The authors isolated and characterized these receptors by using one of the best-studied, biologically relevant, nongenomic steroid-mediated processes: steroid-induced maturation of oocytes (12). The maturation of an oocyte refers to its meiotic stage. ‘‘Immature’’ oocytes are arrested in prophase of meiosis I. Just before ovulation, oocytes are induced to reenter the cell cycle, finally resting in metaphase II. ‘‘Mature’’ oocytes are then competent for ovulation and subsequent fertilization, after which meiosis is completed. Steroid-mediated maturation has been best studied in amphibian and fish oocytes, where progesterone is a potent promoter of oocyte maturation in vitro. In vivo studies designed to directly examine ovarian steroid metabolism and production have demonstrated that, although progesterone promotes maturation in vitro, progesterone metabolites may be the true physiologic mediators of oocyte maturation in vivo. Examples of such biologically produced progesterone metabolites are androstenedione and testosterone in Xenopus laevis (13, 14), 17,20 -dihydroxy-4-pregnen-3-one (17,20 -P) in salmon (15), and 17,20 ,21-trihydroxy-4pregnen-3-one (20 -S) in the Atlantic croaker and spotted sea trout (16).