Extranuclear Steroid Receptors: Nature and Actions

Abstract

Rapid effects of steroid hormones result from the actions of specific receptors localized most often to the plasma membrane. Fast-acting membrane-initiated steroid signaling (MISS) leads to the modification of existing proteins and cell behaviors. Rapid steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this and other ways, the integration of all steroid actions in the cell coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of intense interest, and significant data suggest that extranuclear and nuclear steroid receptor pools are the same proteins. Insights regarding the structural determinants for membrane localization and function, as well as the nature of interactions with G proteins and other signaling molecules in confined areas of the membrane, have led to a fuller understanding of how steroid receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo functions of steroid hormones has been established. Examples include steroid effects on reproductive organ development and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In this review, we highlight the significant progress that has been made in these areas.

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif—Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells

“…Although the underlying mechanism has not been investigated as yet, this observation is consistent with the existence of repeated cyclic interactions between ERα and cognate partners during target gene transactivation, a concept developed by several authors [31,42,43], is implicated in this dynamic LxxLL-coactivator recruitment is unknown. Investigating such a possibility seems to us of primary importance.…”

Estrogen actions on mitochondria—Physiological and pathological implications

“…Studies support mitochondrial trafficking of an increasing number of nuclear receptors and transcription factors including ERα, ERβ, thyroid hormone receptor, glucocorticoid receptor, Nur 77, PPARgamma 2, RXR, RAR, AR, A-RAF, telomerase, Connexin 43, AP1, CREB, NF-k B, p53, c-Myc, HMGA1, TFAM, TFB1M, and TFB2M (Rodrigues-Sinovas et al, 2006;Yuryev et al, 2000;Santos et al, 2006;Hammes and Levin, 2007;Lee et al, 2007;. How they are targeted is not discerned, but most contain at least one F/LXXLL motif and/or are bound by Hsp90/70 in the cytosol.…”

“…Our studies indicate ERβ, along with Tom20 and/or Hsp90 are localized to the mitochondria (Figure 2). Since studies purport that ER functions in the mitochondria, then ERβ should be targeted to either Tom20 or Tom70 receptors (Hammes and Levin, 2007). Receptor preference may depend on ligand induced conformational change in the receptor, and studies show that estrogen increases mitochondria localization of ERβ (Chen et al, 2004a).…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…However, recently the FASEB steroid signaling work group suggested that "membrane-initiated steroid signaling" and "nuclear-initiated steroid signaling" are more appropriate terminologies (Hammes and Levin, 2007). The nuclear-effects on a variety of tissues that involves gene stimulation as well as gene repression (Herbison, 1998, Couse and Korach, 1999, Nilsson et al, 2001, Stossi et al, 2006, Kininis et al, 2007.…”

“…It has become clear that there are "indirect" genomic actions of estrogen in the brain that do not require nuclear targeting of estrogen receptors and therefore are classified as "membraneinitiated" signaling of estrogen (for review (Kelly and Levin, 2001, Bryant et al, 2006, Hammes and Levin, 2007). Such signals that are initiated by E2 at the plasma membrane can trigger intracellular signaling events that result in gene transcription.…”