Non-genomic effects of corticosteroids

Current evidence indicates that the small population of ERalpha and ERbeta localized at the plasma membrane exists within caveolar rafts, interacting with specific membrane proteins ( Membrane association of estrogen receptor alpha and beta influences 17beta-estradiol-mediated cancer cell proliferation, 2008 ). ERalpha can further associate with specialized proteins including the modulator of the non-genomic activity of estrogen receptor ( MNAR ), Shc , EGFR and IGF -1R , and striatin . Shc and striatin have been reported to interact with the A/B domain of ERalpha , while MNAR acts as an adapter coupling ER to "Src": http:///wiki/Src_%28gene%29 .
Palmitoylation enables ERalpha to reside at the plasma membrane and to interact with caveolin-1. Upon E2 binding, ERalpha undergoes slow de-palmitoylation and dissociates from caveolin-1, facilitating ERalpha movement to other membrane micro-domains. Thus, ERalpha could be re-located by docking to other partner proteins (., Shc/IGF-1 receptor and Src/p85).
ERK /MAPK and PI3K /AKT pathways, rapidly activated by ERalpha–E2 complex, also have a critical role in E2 action as a survival agent. In fact, these pathways enhance the expression of the anti-apoptotic protein Bcl-2 , block the activation of the p38/MAPK , reduce the pro-apoptotic caspase-3 activation, and promote G1-to-S phase transition via the enhancement of the cyclin D1 expression ( Distinct nongenomic signal transduction pathways controlled by 17beta-estradiol regulate DNA synthesis and cyclin D(1) gene transcription in HepG2 cells, 2002 ; Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer, 2000 ; Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity, 2001 ; Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling, 2005 ).
On the other hand, E2 induces ERbeta de-palmitoylation and increases ERbeta level and its association with caveolin-1 . As a whole, these data raise the intriguing possibility that the short A/B domain of ERbeta could facilitate the E2-induced association between ERbeta and caveolin-1, impairing its association with MNAR and Src. However, E2 increases the association of ERbeta to a cytosolic kinase, p38 kinase, a member of the mitogen-activated protein kinase (MAPK) family, inducing p38 activation .

The carboxy-terminal hormone-binding domain of the TRα gene is alternatively-spliced to generate several protein products (Figure 3d-2, below). One variant, referred to as α-2, is identical to TRα-1 through the first 370 amino acids, but then its sequence diverges completely, owing to splicing of alternate exons (44-47). Another splicing variant, referred to as TRvII or α-3, is similar to α-2 except that it lacks the first 39 amino acids found in the unique region of α-2 (45). α -2 cannot bind TH because of the replacement of critical amino acids at the extreme carboxy-terminal end of the protein due to alternative splicing (48), and thus cannot mediate ligand-dependent gene transcription (49– 51). The amino acid replacements in α-2 also alter its dimerization properties and reduce DNA-binding affinity (52-55). The α-2 splicing variant is highly expressed in many tissues such as brain, testis, kidney, and brown fat, but its function remains poorly understood (56). The α-2 isoform has been proposed to be an endogenous inhibitor of TH receptor function as it inhibits TRα and β activity in transient gene expression assays (44,54). The mechanism by which α-2 antagonizes TR action is controversial. Some studies indicate that α-2 competes for active receptor complexes at DNA target sites (57,58). Other studies indicate that α-2 inhibits TR activity independent of DNA-binding (59). It is likely that the inhibitory effects of α-2 involve more than one mechanism. Amino acid substitutions in the carboxy-terminal region of α-2 also prevent its interactions with transcriptional corepressors (see below) (55), and may provide an explanation as to why α-2 is not a more potent inhibitor of TR activity. Additionally, the phosphorylation state of α-2 may modulate its inhibitory activity (60). Given the foregoing features, the TRα-1 and α-2 system represents one of the few examples in mammals whereby multiple mRNAs generated by alternative splicing encode proteins that are antagonistic to each other.

Calcium metabolism appears to underlie neuronal cell death via excitotoxicity, [103] [104] [105] [106] and hormonally active vitamin D confers a protective effect in vitro at physiologically relevant concentrations up to 100nM but not above. [107] This mechanism of protection appears to be mediated via a downregulation of L-type voltage-sensitive Ca 2+ ion channels, [107] an effect which has also been seen in bone cells. [108] [109] These L-type channels have been implicated in excitotoxicity. [110] [111]

Non-genomic effects of corticosteroids

non-genomic effects of corticosteroids


non-genomic effects of corticosteroidsnon-genomic effects of corticosteroidsnon-genomic effects of corticosteroidsnon-genomic effects of corticosteroidsnon-genomic effects of corticosteroids