Trends in Pharmacological Sciences
ReviewNon-genomic Effects of Glucocorticoids: An Updated View
Section snippets
Mechanism of Action of GCs
GCs primarily mediate their effects by activating the ubiquitously expressed intracellular GC receptor (GR; see Glossary) [1]. In its inactive state, the GR resides in the cytoplasm and, upon ligand activation, it translocates to the cell nucleus to interact with GC response elements, thereby producing genomic actions that alter protein expression. Interestingly, evidence suggests that GCs also manifest almost immediate non-genomic actions on several signaling processes [2]. GC non-genomic
GCs Exert Rapid Effects on Levels of Intracellular Calcium
Studies suggest that GC rapidly (within seconds) modulates basal intracellular calcium ([Ca2+]i) levels and agonist-induced calcium mobilization (Tables 2 and 3 ).
GCs Rapidly Modulate Skeletal and Smooth Muscle Function
Several studies have reported variable acute effects of GCs on muscle reactivity and tone. The specific example of airway smooth muscle (ASM) cells in the pathogenesis of inflammatory diseases is highlighted in Box 1. In mouse skeletal myotubes (C2C12 immortalized myoblasts), treatment with dexamethasone (for less than 20 min) reduced glucose uptake induced by electrical pulse stimulation-mediated contraction, in a Ca2+/calmodulin protein kinase II (CaMKII)- and AMP-activated protein kinase
GCs Exert Rapid Effects on Reactive Oxygen Species/Reactive Nitrogen Species
Studies demonstrated a rapid effect of GCs on reactive oxygen species (ROS) generation and the involvement of nitric oxide (NO) in mediating some GC effects. An example of the role NO/ROS in the pathogenesis of inflammatory disease is highlighted in Box 2. In breast cancer cells, cortisol rapidly increased levels of ROS and reactive nitrogen species (RNS) (as early as 15 min) and induced DNA damage. The GR antagonist RU486 blocked the cortisol effect, while Nω-nitro-l-arginine methyl ester
GCs Exert Acute Effects on Inflammatory and Apoptotic Pathways
Evidence shows rapid non-transcriptional actions of GCs on inflammation both in transformed cells and immune cells. In transformed cells, such as A549 adenocarcinoma cells, acute exposure (as early as 1 min) to dexamethasone rapidly inhibited epidermal growth factor (EGF)-induced arachidonic acid release, an important mediator of inflammation [36]. This inhibitory effect was due to hindering the recruitment of Grb2, p21ras, and Raf to the EGF receptor (EGFR) through a GR-dependent
Potential Role of a Putative mGR in Mediating the Rapid Effects of GCs
As described previously, the rapid non-genomic effects can, at least in part, be mediated through a putative mGR. Over the years, caveolin-1 (Cav-1), the major protein component of caveolae, has been implicated as a scaffold for the organization of several cytoplasmic signal complexes at the plasma membrane 54, 55. In lung epithelial cells (A549), dexamethasone treatment leads to a rapid (within 2 min) phosphorylation of Cav-1 and protein kinase B (PKB)/Akt in a Src-dependent manner [56].
Concluding Remarks and Future Perspectives
Although we have some insight into how GCs regulate different signaling pathways in a non-genomic manner, future in-depth investigations are warranted to further unravel details of these complex interactions. Indeed, key questions (see Outstanding Questions) still need careful consideration, and additional research must address several important issues: (i) the differential nature of non-genomic effects of GC in immune cells versus non-immune/structural cells; (ii) differences between
Acknowledgments
This work was funded by National Institutes of Health grants 7R01HL111541-07 (O.T.), HL 2P01HL114471-06 (R.A.P.), and GM107094 (R.O.).
Glossary
- Calcium mobilization
- intracellular process triggered by external stimuli (e.g., contractile agonists) where calcium is released to be engaged in different cellular functions such as increased muscle reactivity and contraction. Calcium is usually acquired from extracellular sources (calcium influx) or intracellular stores (e.g., endoplasmic reticulum).
- Genomic action
- action that modulates the expression of genes. It involves transcriptional processes where an activated transcriptional factor
References (66)
- et al.
6. Asthma
J. Allergy Clin. Immunol.
(2003) - et al.
Non-genomic glucocorticoid effects to provide the basis for new drug developments
Mol. Cell. Endocrinol.
(2006) Rapid anti-secretory effects of glucocorticoids in human airway epithelium
Steroids
(2006)- et al.
Nongenomic effects of aldosterone on Ca2+ in M-1 cortical collecting duct cells
Kidney Int.
(2000) A rapid, nongenomic action of glucocorticoids in rat B103 neuroblastoma cells
Biochim. Biophys. Acta
(2002)Acute effects of glucocorticoids on ATP-induced Ca2+ mobilization and nitric oxide production in cochlear spiral ganglion neurons
Neuroscience
(2005)Gene expression of P2X-receptors in the developing inner ear of the rat
Neurosci. Lett.
(1999)P2X receptor immunoreactivity in the rat cochlea, vestibular ganglion and cochlear nucleus
Hear. Res.
(1999)Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes
Arch. Biochem. Biophys.
(2016)Glucocorticoid decreases airway tone via a nongenomic pathway
Respir. Physiol. Neurobiol.
(2012)
Rapid inhibitory effect of glucocorticoids on airway smooth muscle contractions in guinea pigs
Steroids
Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells
J. Biol. Chem.
Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness
Trends Pharmacol. Sci.
Rapid activation of ERK1/2 mitogen-activated protein kinase by corticosterone in PC12 cells
Biochem. Biophys. Res. Commun.
Corticosterone-induced rapid phosphorylation of p38 and JNK mitogen-activated protein kinases in PC12 cells
FEBS Lett.
Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells
Blood
Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions
Biochim. Biophys. Acta
The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells
Mol. Cell. Endocrinol.
Import of the glucocorticoid receptor into rat liver mitochondria in vivo and in vitro
J. Steroid Biochem. Mol. Biol.
Developmental shift in TcR-mediated rescue of thymocytes from glucocorticoid-induced apoptosis
Immunobiology
Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells
Immunobiology
Estrogen- and xenoestrogen-induced ERK signaling in pituitary tumor cells involves estrogen receptor-alpha interactions with G protein-alphai and caveolin I
Steroids
Membrane glucocorticoid receptor activation induces proteomic changes aligning with classical glucocorticoid effects
Mol. Cell. Proteomics
Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator of the immune system?
Brain Behav. Immun.
Rapid and non-genomic reduction of intracellular [Ca(2+)] induced by aldosterone in human bronchial epithelium
J. Physiol.
Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes
Biochem. J.
Inhibition of ATP-induced calcium influx in HT4 cells by glucocorticoids: involvement of protein kinase A
Acta Pharmacol. Sin.
Cortisol rapidly reduces prolactin release and cAMP and 45Ca2+ accumulation in the cichlid fish pituitary in vitro
Proc. Natl. Acad. Sci. U. S. A.
Decreased sodium-potassium and calcium adenosine triphosphatase activity in asthma: modulation by inhaled and oral corticosteroids
Indian J. Chest Dis. Allied Sci.
Glucocorticoid modulation of Ca2+ homeostasis in human B lymphoblasts
J. Physiol.
Rapid non-genomic inhibition of ATP-induced Cl− secretion by dexamethasone in human bronchial epithelium
J. Physiol.
Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells
Circ. Res.
Stimulation of the phosphoinositide signalling system as a possible mechanism for glucocorticoid action in blood pressure control
J. Hypertens. Suppl.
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