Journal of Allergy and Clinical Immunology
Interactions iith Other Signaling MechanismsMolecular interactions between glucocorticoids and long-acting β2-agonists☆,☆☆
Section snippets
Mechanisms of glucocorticoid action
Endogenous glucocorticoids regulate the body's normal reactions to stress, preventing those reactions from overshooting and threatening homeostasis.4 Thus, many of the physiologic and pharmacologic effects of glucocorticoids may be secondary to modulation of the action of numerous intercellular and intracellular mediators, including other hormones, prostaglandins, lymphokines, and bioactive peptides.5 Glucocorticoids act by influencing transcription of target genes.6 Glucocorticoids freely
Effects of GR phosphorylation status on GR function
GR is a phosphoprotein containing 64 potential phosphorylation sites,13 including those for extracellular signal-regulated kinase (ERK, 8 sites), p38 mitogen-activated protein kinase (MAPK, 1 site), glycogen synthase kinase-3 (8 sites), protein kinase C (PKC, 9 sites), and protein kinase A (PKA, 8 sites). Importantly, GR has 3 ERK binding sites (Fig 2).
Mechanisms of β-Agonist action
Ligand binding to the β2-adrenergic receptor (β2AR) results in activation of receptor-associated Gs proteins and enhanced coupling with adenylyl cyclase.3 The coupling of activated Gs and adenylyl cyclase leads to enhanced production of cyclic AMP (cAMP) and subsequent activation of cAMP-dependent PKA, which then phosphorylates and thus inactivates myosin light chain kinase, preventing myosin phosphorylation. Concomitant activation of calcium-magnesium exchange ATPases in the endoplasmic
Effects of LABA on GR function: possible role of GR phosphorylation
In an important in vitro study, Eickelberg et al38 found that in primary human lung fibroblasts and vascular smooth muscle cells both salbutamol and salmeterol could induce GR nuclear translocation and enhance GR-GRE binding in the absence of ligand. Translocation of GR by β2-agonists was less effective than that seen with dexamethasone and was PKA dependent. This study has since been confirmed in preliminary reports in vivo,39, 40, 41 which have indicated that salmeterol can induce GR nuclear
Up-regulation of receptor number
Dexamethasone, a synthetic glucocorticoid, increases the number of β2ARs in human lung measured by radioligand binding.46 Several putative GREs have been identified in the promoter sequence of the human β2AR gene,47 and increased β2AR gene transcription occurs after dexamethasone treatment through a GRE in the 5′-flanking region of the gene36 in human lung tissue. This increase in transcription is both time-dependent and dose-dependent, consistent with the later induction of receptor binding
Conclusions
LABAs may affect GR nuclear localization through modulation of GR phosphorylation and, further, may prime GR functions within the nucleus by modifying GR or GR-associated protein phosphorylation. Glucocorticoids may in turn regulate β2AR function by increasing expression, acting through GREs, and, importantly, by restoring G-protein-β2AR coupling and inhibiting β2-AR down-regulation, thereby preventing desensitization.
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Work within the laboratory is funded by The Clinical Research Committee (Royal Brompton Hospital), The British Lung Foundation, GlaxoSmith-Kline, and Innovata Biomed. K.M. is funded by the Thai Government, and O.U. is funded by GlaxoSmithKline.
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Reprint requests: Ian M. Adcock, PhD, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse St, London SW3 6LY, UK.