Non-genomic steroid hormone effects: Membrane or intracellular receptors?

doi:10.1016/j.jsbmb.2006.09.016

The Journal of Steroid Biochemistry and Molecular Biology

Volume 102, Issues 1–5, December 2006, Pages 180-183

https://doi.org/10.1016/j.jsbmb.2006.09.016 Get rights and content

Abstract

A controversy regarding the identity of receptors that mediate nongenomic, transcription-independent cellular responses to steroids is presently attracting considerable scientific interest. While there is strong evidence for classic receptors belonging to the nuclear receptor superfamily to mediate nongenomic steroid effects in some cases, it does not exist for others. Nongenomic estrogen effects seem to predominantly involve classical estrogen receptors, both residing in cytoplasm and at the cell membrane. On the other hand, there is increasing evidence for the existence of nonrelated membrane receptors for estrogens, mediating CNS effects. Novel membrane receptors for other steroids have been recently cloned, with the demonstration of their biological relevance still largely pending. Recent findings on new and unexpected properties of classic receptors have partially deflected the interest from novel, nonclassic membrane receptors, which are being progressively identified at present. In addition, new findings pose challenges to some of the conclusions drawn from earlier experiments, and potential involvement of receptors and mechanisms of action need to be reconsidered.

To know the nature of receptors involved will be key to beneficial medical translation of specific and targeted steroid responses. Differential pharmacological exploitation of different steroid receptors seems to become a tangible option.

Introduction

While the existence of nongenomic, mostly rapid actions of steroids has been widely accepted by the scientific community, the range of receptors that participate in such phenomena has always been controversial. In the light of new, unexpected findings about the properties and actions of steroid receptors that belong to the superfamily of nuclear receptors, the existence of further proteins unrelated to this family and acting as “nonclassic” receptors has even been questioned. Furthermore, the physiological implications are not yet clear in many cases.

The earliest reports on nongenomic reponses to steroid hormones date back to the 1940s. Meanwhile, numerous examples are known on the cellular level, along with a smaller number of phenomena that were demonstrated in living organisms. Examples which have been studied in most detail include the acrosome reaction in sperm, which is triggered by progesterone [1], and the rapid activation of endothelial NO synthase by estrogens (for review see, e.g. [2]).

Rapid, nongenomic responses to steroids often occur via second messenger cascades, which in turn originate from signalling complexes located at membranes. Consequently, receptors for rapid steroid action are widely believed to be membrane-associated or integrated into to the membrane. Often, though not always, rapid effects have been elicited by steroid conjugated to a presumably membrane-impermeable carrier, which has been taken as evidence for plasma membrane localization. However, such experiments have several drawbacks.

From the evolutionary point of view, nature has developed a signaling pathway that does exclusively rely on transmembrane receptor kinases in the plant kingdom, which uses brassinosteroids for signalling. Although there are no closely related orthologs in the animal kingdom to the brassinosteroid sensing proteins, their existence illustrates the wide variety of steroid signal pathways.

In the following section we want to briefly review evidence for classic and nonclassic receptors in various examples of nongenomic responses.

Section snippets

Classic receptors

Estrogen actions probably comprise the area where the largest number of phenomena has been described with robust evidence for the participation of classic receptors. Although it is still controversial whether the full length ERα (estrogen receptor) or a shortened variant termed ER46 is required for the rapid nontranscriptional activation of endothelial NO synthase by estradiol [3], ER overexpression has been demonstrated to dramatically enhance the response. There is evidence that

Nonclassic receptors

As mentioned earlier, the signalling way via receptor kinases that are not related to the superfamily of (animal) nuclear receptors, appears to be the only pathway in plants. Although this is not paralleled in the animal kingdom, it thus can be regarded as a mechanism developed early in evolution. In the animal kingdom, steroids are used widely as well. Insects use ecdysteroids, which bind to ecdysteroid receptors, related to mammalian nuclear receptors. However, a G-protein coupled receptor

Synopsis

When browsing the literature on steroid effects over the past six decades, the attentive reader will find not so few examples for responses that now would be classified nongenomic, although particularly in elder work, such distinction could not be made as no mechanism for steroid action had been defined at all. The initial question, do membrane receptors exist that mediate nongenomic action, has been readily answered for the first rapid steroid effect ever reported to our knowledge,

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^☆: Lecture presentation at the 17th International Symposium of the Journal of Steroid Biochemistry; Molecular Biology, Recent Advances in Steroid Biochemistry and Molecular Biology (Seefeld, Tyrol, Austria, 31 May–3 June 2006).

¹: At present, the corresponding author is employed by AstraZeneca R&D while on leave from his professorship at the University of Heidelberg.

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Non-genomic steroid hormone effects: Membrane or intracellular receptors?☆

Abstract

Introduction

Section snippets

Classic receptors

Nonclassic receptors

Synopsis

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Steroids

Trends. Pharmacol. Sci.

J. Biol. Chem.

Steroids

Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean?

Circ. Res.

Integration of the extranuclear and nuclear actions of estrogen

Mol. Endocrinol.

Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade

Proc. Natl. Acad. Sci. USA

Estren (4-estren-3alpha, 17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor

Mol. Endocrinol.

Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha, 25(OH)2vitamin D3

Steroids

Rapid modulation of osteoblast ion channel responses by 1alpha, 25(OH)2-Vitamin D3 requires the presence of a functional Vitamin D nuclear receptor

Proc. Natl. Acad. Sci. USA

Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model

Nat. Rev. Drug. Discov.

Rapid, nongenomic responses to ecdysteroids and catecholamines mediated by a novel Drosophila G-protein-coupled receptor

J. Neurosci.