Non-genomic Effects of Glucocorticoids: An Updated View

Abstract

Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs 'rapidly' enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.

Keywords: airway remodeling; asthma; corticosteroids; glucocorticoid receptor; non-genomic; smooth muscle.

Figure 1.. Acute non-genomic effects of GCs on basal and agonist-induced Ca²⁺ responses.

GCs have been described to differentially affect basal intracellular Ca²⁺ ([Ca²⁺]i) homeostasis. Depending on the cell type studied and GC applied, GCs can either reduce or augment basal [Ca²⁺]i. (A) GCs may decrease [Ca²⁺]i by activating AC/PKA mediated mechanisms, likely through events taking place at the cell membrane level and independent of GR stimulation, ultimately leading to SERCA activation (thapsigargin-sensitive Ca²⁺-ATPase). (B) Conversely, GCs can activate PLC/IP3 and PKC dependent signaling cascades resulting in enhanced basal [Ca²⁺]i; the involvement of GR in this process is currently unknown. (C) Agonist-induced increases in [Ca²⁺]i can be counteracted by GC-mediated activation of AC/PKA-induced stimulation of SERCA pumps as described in ATP stimulated cells. In contrast, a functional role for PKC was determined in the effects of GC on serotonin-induced Ca²⁺ responses, suggesting that the acute inhibitory mechanisms of GCs are highly agonist specific. (D) Limited studies are available on acute potentiating effects by GCs on agonist-induced Ca²⁺ responses; in neuronal cells it was suggested that these effects are mediated via the rapid activation of Ca²⁺-influx through ionotropic ATP-gated purinergic 2X receptors. Whether glucocorticoid-mediated membrane receptors are involved in this pathway remains to be further investigated (mGR?). These responses rely on the presence of external Ca²⁺. Abbreviations: AC, adenylyl cyclase; AR, agonist receptor; IP3, inositol 1, 4, 5-triphosphate; GC, glucocorticoid; mGR, membrane glucocorticoid receptor; PKA, protein kinase A; PKC, protein kinase C; SERCA, sarco/endoplasmatic reticulum Ca²⁺ -ATPase.