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Nongenomic actions of steroid hormones

Key Points

  • teroids might exert their actions by delayed genomic (classical) mechanisms, as well as by rapid, nongenomic pathways.

  • Nongenomic action might occur in seconds or minutes.

  • Nongenomic action includes many second messengers (inluding cAMP and diacylglycerol), kinases (mitogen-activated protein kinase, protein kinase C) and ion fluxes (calcium).

  • The pharmacological profiles (agonist and/or antagonist selectivity) often differ markedly between the classical and nongenomic mechanisms.

  • The identities of the receptors that are involved in nongenomic steroid actions are not yet elucidated.

  • In some cases, classical, nuclear steroid receptors have been shown to drive signalling pathways such as kinase cascades.

  • Gene transcription and nongenomic responses might modulate each other by crosstalk.

  • Nongenomic steroid actions have been observed in humans (and many other vertebrates) and are probably clinically relevant.

  • More models, such as classical-receptor knockout animals, are required to identify or rule out the receptors that are involved.

  • Future research might widen the selection of tools, such as specific antagonists, to further explore the implications of in vivo nongenomic steroid effects and their possible therapeutic use.

Abstract

Steroid hormones modulate many physiological processes. The effects of steroids that are mediated by the modulation of gene expression are known to occur with a time lag of hours or even days. Research that has been carried out mainly in the past decade has identified other responses to steroids that are much more rapid and take place in seconds or minutes. These responses follow nongenomic pathways, and they are not rare.

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Figure 1: Nongenomic actions of the progesterone receptor.
Figure 2: Rapid changes in nuclear pore structure induced by aldosterone.
Figure 3: Flexibility of vitamin D.
Figure 4: Activation pathways of the MAPK cascade in response to vitamin D.
Figure 5: The thyroid hormones.
Figure 6: Scheme for the numerous actions of steroids by different pathways.

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Acknowledgements

The authors apologize to all researchers who have made important contributions to the field but who could not be included in the reference list owing to space constraints.

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Correspondence to Martin Wehling.

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41580_2003_BFnrm1009_MOESM1_ESM.jpg

Online figure 1 | Rapid calcium effects of aldosterone in endothelial cells. Porcine endothelial cells before and 5 min after addition of aldosterone. Calcium was quantified by Fura-2 imaging. In these cells, the increase in [Ca2+]i caused by aldosterone stimulation occurs predominantly near the cell membrane, which indicates influx from the extracellular space as the predominant mechanism, whereas in other cells it is mainly intracellular calcium stores that are involved. Modified with permission from Ref. 50 © (1994) Elsevier Science. (JPG 26 kb)

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DATABASES

InterPro

SH3

Swiss-Prot

25Dx

eNOS

ERα

ERβ

Progesterone-binding protein

vitamin D receptor

XPR

FURTHER INFORMATION

Martin Wehling's laboratory

The Nomenclature of Steroids

Rapid Responses to Steroid Hormones

Glossary

ERYTHROCYTE

A mature red blood cell, which lacks a nucleus and mitochondria. It contains haemoglobin and functions in the transport of oxygen.

ACROSOME REACTION

On appropriate stimulation, the outer acrosomal membrane at the front of the sperm head ruptures and liberates its contents (mainly enzymes and actin). An early event in the reaction is a rapid increase in the concentration of intracellular calcium that can be measured easily.

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

MICROSOME

A small, heterogeneous vesicular particle, 50–150-nm wide, that is the product of homogenization of eukaryotic cells. Rough microsomes, which have ribosomes attached to their surface, are derived from the rough endoplasmic reticulum, whereas smooth microsomes lack ribosomes and might be derived from the smooth endoplasmic reticulum or the plasma membrane.

RU486

(Mifepristone). A steroidal progesterone receptor- and glucocorticoid receptor-antagonist that prevents implantation of a fertilized ovum in the uterus.

GRANULOSA CELL

A cell that makes up a layer that surrounds the cavity of mature Graafian and secondary follicles. It catalyses the conversion of androgens to oestrogen.

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It activates Gi proteins by catalysing the ADP ribosylation of the α-subunit.

CAVEOLAE

Specialized rafts that contain the protein caveolin and form a flask-shaped, cholesterol-rich invagination of the plasma membrane. Caveolae might mediate the uptake of some extracellular materials, and are probably involved in cell signalling.

ATOMIC-FORCE MICROSCOPY

A microscope that nondestructively measures the forces (at the atomic level) between a sharp probing tip (which is attached to a cantilever spring) and a sample surface. The microscope views structures at the resolution of individual atoms.

INOTROPIC

Influencing the contractility of muscles.

OPIOID RECEPTORS

These seven transmembrane receptors are produced at high levels in the nervous system and are important for modulating pain responses. The κ-type inhibits a G-protein-modulated calcium channel.

DEXAMETHASONE

A synthetic glucocorticoid that has actions similar to the adrenal corticosteroids. It has negligible mineralocorticoid activity.

DIASTEREOMER

Any stereoisomer of a given molecule that does not represent its exact mirror image.

PROTEOGLYCAN

A class of acidic glycoproteins that contain more carbohydrate than protein.

CHONDROCYTE

A differentiated cell of cartilage tissue.

STATS

A family of cytoplasmic transcription factors (signal transducers and activators of transcription) that dimerize on phosphorylation and translocate to the nucleus to activate transcription of target genes.

ELECTROENCEPHALOGRAM

A recording of the electrical activity of different parts of the brain.

BARBITURATES

Pharmacologically active molecules with a potent depressor effect in the central nervous system.

VENTRAL TEGMENTAL AREA

A nucleus of the midbrain. The main supplier of dopamine to the cortex.

VENTROMEDIAL HYPOTHALAMUS

An area of the brain that is found in the middle region of the hypothalamus. It is important for the regulation of appetite and other consummatory behaviours.

PREGNENOLONE

A key intermediate in the biosynthetic pathway from cholesterol to progesterone.

CREB

Cyclic AMP response-element-binding protein. A transcription factor that functions in glucose homeostasis and growth-factor-dependent cell survival, and has also been implicated in learning and memory.

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Lösel, R., Wehling, M. Nongenomic actions of steroid hormones. Nat Rev Mol Cell Biol 4, 46–55 (2003). https://doi.org/10.1038/nrm1009

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