Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

Key Points Steroid receptors classically function in the nucleus, regulating the expression of genes that are important for a wide range of cellular functions. It has now become clear that many classic steroid receptors also localize to other cellular compartments (including, prominently, the plasma membrane) to activate various signalling pathways. Signalling from membrane-localized steroid receptors can elicit non-genomic responses, such as G protein and kinase signalling. Steroid receptor signalling from the membrane can also be involved in the regulation of gene expression, sometimes by engaging in crosstalk with nuclear pools of the respective receptor. Membrane-initiated steroid signalling has been shown to have various physiological functions and has been associated with the development and propagation of cancer. Transgenic mice that selectively express only one functional oestrogen receptor-α pool — either membrane or nuclear — display phenotypes that overlap significantly with those of mice completely lacking oestrogen receptor-α, indicating that both pools are necessary for most oestrogen-dependent processes. More broadly, it can be concluded that extranuclear steroid signalling is required for full steroid hormone action during development and organ homeostasis. Steroid hormone receptors are well known to regulate various aspects of animal physiology by acting as transcriptional regulators in the nucleus. However, it is now evident that these receptors can also be targeted to extranuclear locations (such as the plasma membrane), where they instigate rapid signals that contribute to steroid-mediated cellular responses. Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health