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Vol. 52, Issue 4, 513-556, December 2000
A Focus on Rapid,
Nongenomic Effects
Institute of Clinical Pharmacology, Faculty for Clinical Medicine
at Mannheim, University of Heidelberg, Mannheim, Germany
I. Introduction and Historical Development
II. How Do Steroids Act?
A. Genomic Steroid Action
B. Nongenomic Steroid Action
III. Steroid Receptors Mediating Genomic and Nongenomic Steroid
Action
A. Receptors Responsible for Genomic Steroid Action
1. Structural Features of Steroid Hormone Receptors.
2. Genomic Steroid Hormone Action.
3. Steroid Hormone-Responsive Elements.
4. Steroid-Induced Initiation of Transcription.
5. Alternative, Including Nontranscriptional Actions of
Ligand-Steroid Hormone Receptor Complexes.
B. Receptors Responsible for Nongenomic Steroid Action
1. Classic Intracellular Receptors (Classification AIIa).
2. Nonclassic Steroid Receptors
No Coagonist Required
(Classification AIIb).
3. Nonclassic Steroid ReceptorsCoagonist-Mediated Steroid Action
(Classification BIIb).
4. No Receptor InvolvedDirect Nongenomic Action (Classification
AI).
IV. Steroid Groups
A. Gonadal Steroids
1. Progesterone.
a. Rapid Effects of Progesterone.
b. Progesterone Receptors for Rapid Signaling.
2. Estrogens.
a. Rapid Effects of Estrogens.
b. Estrogen Receptors for Rapid Signaling.
3. Androgens.
a. Rapid Effects of Androgens.
b. Androgen Receptors for Rapid Signaling.
B. Glucocorticoids
1. Rapid Effects of Glucocorticoids.
2. Glucocorticoid Receptors for Rapid Signaling.
C. Mineralocorticoids
1. Rapid Effects of Mineralocorticoids.
2. Mineralocorticoid Receptors for Rapid Signaling.
D. Neuroactive Steroids
1. Rapid Effects of Neuroactive Steroids.
2. Neurosteroid Receptors for Rapid Signaling.
a. 
-Aminobutyric AcidA Receptor.
b. N-Methyl-D-aspartate Receptor.
c. Sigma1 Receptor.
d. 5-Hydroxytryptamine Type 3 Receptor.
e. Glycine Receptor.
E. Vitamin D3
1. Rapid Effects of Vitamin D3.
2. Vitamin D3 Receptors for Rapid Signaling.
F. Triiodothyronine
1. Rapid Effects of Triiodothyronine.
2. Triiodothyronine Receptors for Rapid Signaling.
V. Two-Step Model for Steroid Action
VI. Clinical Perspectives
A. Cardiovascular Pharmacology
B. Reproductive Pharmacology
C. Endocrinological Pharmacology
D. Neuro-/Psychopharmacology
VII. Conclusions and Outlook
Acknowledgments
References
According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D3 derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D3 and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.
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