Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

Abstract

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 and disease.

Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction

“…Even with all this complexity, activation of intracellular ERs is only one of the major mechanisms of estradiol action. Estradiol mediates a variety of other responses, many of which are initiated at the membrane surface, across neuronal and non-neuronal tissue [5]. Within the nervous system, rapid estradiol action was first demonstrated in preoptic/septal neurons, where changes in electrophysiological properties were observed within seconds of estradiol exposure [6].…”

The Substitution Principle within the REACH Regulation: Nuclear Receptor-Bound Endocrine Disruptors

“…Hence, they allow to integrate different, multiple signals between central and peripheral organs orchestrating hormone-dependent signaling and also acting as xenosensors. NRs are located within the cell, shuttling among different intracellular compartments although the best of our knowledge is related to its nuclear localization [9,15].…”

“…Others, such as the ER , are located as monomers primarily in the nucleus, although a small percentage may also be bound to HSPs in the cytoplasm [15].…”

“…The E domain also contains a ligand-binding sequence that structurally differs in different receptors to confer specificity to ligands and antagonists. Overall, these domains contribute to the ligandinduced changes in gene expression occurring through the combined action of co-regulators and NRs bound at specific DNA sites [9,15].…”

Chemical control over membrane-initiated steroid signaling with a DNA nanocapsule

“…We have applied this technology to estradiol (E 2 ) as a signaling steroid, as estradiol is important for blood vessel integrity in endothelial cells, cell proliferation in cancer, and neurotransmission (7,18). We designed and synthesized chemically caged E 2 by covalently attaching the 3′ position of E 2 to dextran through a disulfide linkage.…”