Rapid Actions of Steroid Receptors in Cellular Signaling Pathways

Abstract

Steroid hormones regulate cellular processes by binding to intracellular receptors that, in turn, interact with discrete nucleotide sequences to alter gene expression. Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. This process typically takes at least 30 to 60 minutes. In contrast, other regulatory actions of steroid hormones are manifested within seconds to a few minutes. These time periods are far too rapid to be due to changes at the genomic level and are therefore termed nongenomic or rapid actions, to distinguish them from the classical steroid hormone action of regulation of gene expression. The rapid effects of steroid hormones are manifold, ranging from activation of mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins). In some cases, these rapid actions of steroids are mediated through the classical steroid receptor that can also function as a ligand-activated transcription factor, whereas in other instances the evidence suggests that these rapid actions do not involve the classical steroid receptors. One candidate target for the nonclassical receptor-mediated effects are G protein-coupled receptors (GPCRs), which activate several signal transduction pathways. One characteristic of responses that are not mediated by the classical steroid receptors is insensitivity to steroid antagonists, which has contributed to the notion that a new class of steroid receptors may be responsible for part of the rapid action of steroids. Evidence suggests that the classical steroid receptors can be localized at the plasma membrane, where they may trigger a chain of reactions previously attributed only to growth factors. Identification of interaction domains on the classical steroid receptors involved in the rapid effects, and separation of this function from the genomic action of these receptors, should pave the way to a better understanding of the rapid action of steroid hormones.

Sex-dependent effects of gonadal steroids and cortisol on cardiac contractility in rainbow trout

“…Although several, rapid, nongenomic effects of steroids appear to be mediated through G-protein activation (Cato et al, 2002), this was not the case for the positive inotropic effects of steroids on the trout heart. This disassociation was inferred from the observations that (1) GDP had no independent effects on ventricle strip performance, and all the steroids tested (T, 11KT, C and E2) increased contractile force in strips pre-treated with GDP, and (2) the positive inotropism induced with epinephrine was completely additive to the actions of sex steroids and C. Finally, it will be of interest in future studies to distinguish the separate pathways or mechanisms that sex steroids and C use to modulate cardiac inotropism in male and female rainbow trout.…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…Such signals that are initiated by E2 at the plasma membrane can trigger intracellular signaling events that result in gene transcription. New gene transcription can result from E2 activation of multiple intracellular kinase cascades including MAPK, phosphoinositide 3-kinase (PI3K), cAMP-protein kinase (PKA) and protein kinase C (PKC) pathways (Watters et al, 1997, Bi et al, 2001, Cato et al, 2002, Yang et al, 2003, Deisseroth et al, 2003. These events are often termed rapid signaling cascades because they are initiated at the plasma membrane or in the cytoplasm and occur much faster than ERE-driven events (Bryant et al, 2005, Björnström andSjöberg, 2005).…”

Nontranscriptional actions of the glucocorticoid receptor

“…There is growing evidence that the nontranscriptional actions of several other steroid hormone receptors regulate physiologically important processes [64]. For example, osteocyte apoptosis and bone loss is prevented by the androgen and estrogen steroid receptors through nontranscriptional activation of protein kinase Src and mitogen-activated protein kinase [65,66].…”