Nongenomic actions of androgen in Sertoli cells

Nongenomic actions mediated by androgens have now been described in more than 10 cell types. Some of these cells transduce androgen signals using surface receptors that await final characterization, whereas other cells employ the classical AR. Various second messengers can be activated by androgens, including cAMP, IP3, phospholipase C, DAG, and Ca2+. Each of these second messengers is capable of activating multiple kinases. One of the most important kinase networks to be regulated by androgens is the MAP kinase cascade. This series of kinase reactions is capable of altering the activity of many transcription factors with important implications for the regulation of gene expression. Because there is evidence that androgen is capable of regulating CREB-mediated gene expression via the MAP kinase pathway, it is now somewhat misleading to characterize androgen actions in Sertoli cells as nongenomic. Instead, it may be more appropriate to label these activities as independent of AR-DNA interactions, or more simply as nonclassical. The nonclassical regulation of gene expression in Sertoli cells is particularly relevant for providing an answer to the paradox of how testosterone can support spermatogenesis yet regulate few genes via AR-promoter interactions. It is expected that with the increasing use of microarray and related technologies, additional AR-regulated genes will be identified. However, the androgen-induced increases in [Ca2+]i, the activation of Src kinase, and the MAP kinase cascade that have been characterized thus far have the potential to regulate the expression of many more genes than is possible by direct AR-promoter interactions. Thus, it is likely that nonclassical actions of testosterone in Sertoli cells will be found to be a necessary complement to the classical actions that are required to maintain spermatogenesis.