NOVEL (‘NON-GENOMIC’) ACTIONS OF STEROID HORMONES
FHS Signalling 2011 helen.christian@dpag.ox.ac.uk
GOOD ‘OVERVIEW’ REVIEWS
*suggested priority reading
*Levin ER (2008) Rapid signalling by steroid receptors. Am J Physiol Regul Integr Comp Physiol 295:R1425R1430
Good for covering all steroids and the most up to date
* Losel, R. and Wehling, M. (2003) Nongenomic actions of steroid hormones. Nat. Rev. Mol. Cell Biol. 4, 46-56
Martin Wehling has led the nongenomic field and has written several reviews of the topic. This is the most concise
and readable considering all steroids.
Bjornstrom L (2005) Mechanisms of estrogen signaling: convergence of genomic and nongenomic actions on target
genes. Mol Endocrinol 19:833-842
Good for exploring the nongenomic ER control of transcription of genes that do not contain ERE’s and examples of
ways in which the genomic and nongenomic actions of ERs converge
*Vasudevan, N. and Pfaff, D.W. (2007) Membrane-initiated actions of estrogens in Neuroendocrinology: emerging
principles. Endocr. Rev. 28,1-19
A very thought provoking review that addresses membrane and genomic pathways and how they might function
together in cells. Focuses on estrogen actions in the brain.
Rahman & Christian (2007) Non-classical actions of testosterone: an update. Trends in Endocrinology and Metabolism,
18:371-378
Read if you are interested in testosterone effects specifically
Prossnitz et al (2007) GPR30: A G protein coupled receptor for estrogen. Mol Cell Endocrinol 265-266:138-142
Review of the discovery of GPR30
*Balthazart et al (2000) Fast regulation of steroid biosynthesis. TINS 23:57-8.
This review considers how rapid regulation locally of steroid synthesis may be important for rapid effects
*Funder J 2005The Nongenomic Actions of Aldosterone. Endocr Rev 26(3): 313 - 321.
An excellent ‘must-read’ review which makes a thorough analysis of the evidence for rapid, non-genomic actions of
aldosterone in the vascular wall, heart and kidney. In particular he addresses the question whether the balance of
evidence so far indicates whether non-genomic effects are mediated by the MR or a novel receptor, and he concludes the
former. Funder has a refreshingly direct style of writing.
MEMBRANE STEROID BINDING SITES
Pietras & Szego (1976) Specific binding sites for oestrogen at surface of endometrial cells. Nature 265: 69.
The first experiments demonstrating the concept of steroids binding to surface of cells, previous work by the group had
shown rapid cAMP and calcium responses to estrogen in endometrial cells
Next three papers work from the Levin group looking at classical ER in the plasma membrane and how it gets there:
*Razandi et al (1999) Membrane and nuclear ER originate from 1 transcript. Mol Endocrinol 13:307-319.
The ER overexpression study in CHO cells showing 2% of nuclear amount of ER could be measured in the plasma
membrane
Razandi et al (2002) ERs associate with and regulate production of caveolin. Mol Endocrinol 16:100-115
The study that showed caveolin was required for membrane translocation of ER to caveolae in the membrane of primary
human vascular smooth muscle/breast cancer cell line models
Pedram et al (2007) Mechanism of steroid receptor translocation to the plasma membrane. J Biol Chem 282:22278-88
The paper showing palmitoylation of ER important for its association with the plasma membrane
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GPR30 evidence
Filardo et al (2002) Estrogen action via the G protein coupled receptor GPR30. Mol Endocrinol 16:70-84
*Revankar et al (2005) Estrogen binding GPCR GPR30 identified. Science 307:1625-1630
Martensson U et al (2009) Deletion of the GPR30 impairs glucose tolerance, reduces bone growth and increases blood
pressure. Endocrinology 150:687-698
The first reports linking GPR30 as an estrogen binding receptor in breast cancer lines and a knockout study
MECHANISMS OF RAPID ACTIONS OF SEX STEROIDS
*Kousteni et al (2002) Reversal of bone loss in mice by nongenomic steroid signalling. Science 298:843.
*Vasudevan et al (2001) Rapid estrogenic effects required for genomic actions. PNAS, 98:12267-12271.
‘Proof of concept study’ showing rapid signalling at the membrane potentiates subsequent ‘genomic’ ERE/ER mediated
transcription signalling
*Christian & Morris (2002) Rapid actions of estrogen in the pituitary. J Physiol 539:557-566.
Stevis et al (1999) Differential effects of estrogen conjugates. Endocrinology 140:5455.
The report that showed contamination of E-BSA preparations with free estrogen suggesting studies with E-BSA are
flawed unless extensive controls performed eg. using charcoal stripped E-BSA to remove free.
Glidewell-Kenney et al (2007) Nonclassical estrogen receptor a signalling mediates negative feedback in the female
mouse reproductive axis. Proc Natl Acad Sci 104:8173-77
‘Mutant ERa Knock-in’ NERKI transgenic mouse that is unable to bind DNA reveals non-classical roles..
Pedram et al (2009) Developmental phenotype of a membrane only estrogen receptor α (MOER) mouse. J Biol Chem.
284:3488 Study compares ERα KO to ERα KO mice expressing E domain of ERα at the membrane and finds that major
functions of estrogen are not rescued by membrane ER.
CONCEPT THAT DIFFERENT STEROID RECEPTOR LIGANDS CAN ACTIVATE GENOMIC OR
NONGENOMIC SIGNALLING
Lutz L.B. et al. (2003) Selective modulation of genomic and nongenomic androgen responses by androgen receptor
ligands. Mol. Endocrinol. 17, 1106-1116
Madak-Erdogan et al (2008) Nuclear and extranuclear pathway inputs in the regulation of global gene expression by
estrogen receptors. Mol Endocrinol 22:2116-2127
First report of use of estrogen-dendrimer conjugates that remain outside the nucleus and therefore can only mediate
‘non-genomic effects’, in a breast cancer line 25% of gene expression regulated by the compound.
NEUROSTEROIDS – THE BEST CHARACTERISED ‘NON-GENOMIC’ STEROID ACTIONS
Belelli (2006) Neurosteroids and their physiological significance. Neuroscience 138:821-9 Useful review
[see Seminar Friday]
NON-GENOMIC RAPID ACTIONS OF GLUCOCORTICOIDS
Hinz et al (2000) Rapid non-genomic feedback effects of glucocorticoids on ACTH secretion in rats. Pharm Res
17:1273-1277
Di et al (2003) Non genomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus. J Neurosci
23:4850-57
Evanson et al (2010) Fast feedback inhibition of HPA axis by glucocorticoids is mediated by endocannabinoid
signalling. Endocrinology 151:4811-19
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