Non Genomic Processes

The second, less recognized, route of estrogen action is via a non-transcrip-tional signaling pathway which has been observed in the brain, pituitary, vascular smooth muscle cells, and breast cells [16-18]. Both short-term latency and duration, varying from milliseconds to minutes, are typical for non-tran-scriptional estrogen action. This possible alternative mechanism to the genomic route is described by Moss et al. [15] and Zakon [19],containing both extra- and intracellular non-genomic effects (see Fig. 2).

Extracellular estrogen can bind specific receptors, and subsequently trigger a G-protein-coupled mechanism. The activated G-protein is linked to the enzyme adenylate cyclase (AC), thereby causing the cyclase to produce the second messenger cyclic-AMP (cAMP). In turn this cAMP will activate protein

Fig. 2. Possible mechanism for non-genomic pathways of estrogen signaling, where G is a membrane G-protein, AC is adenylate cyclase, aTp is adenosine triphosphate, AMP is adenosine monophosphate, cAMP is cyclic-AMP, PKA is protein kinase A, and PDE is phosphodiesterase

Fig. 2. Possible mechanism for non-genomic pathways of estrogen signaling, where G is a membrane G-protein, AC is adenylate cyclase, aTp is adenosine triphosphate, AMP is adenosine monophosphate, cAMP is cyclic-AMP, PKA is protein kinase A, and PDE is phosphodiesterase kinase A (PKA), an enzyme which catalyzes the transfer of a phosphate group from adenosine triphosphate (ATP) to a specific protein. Moss et al. [15] suggest that phosphorylation by PKA prolongs the opening of specific ion-channels enhancing the membrane conductance. The second mechanism, involving intracellular estrogen, is not exactly known. But estrogen could reduce the activity of phosphodiesterase (PDE), thus decreasing the breakdown of cAMP to AMP, or assist in releasing more cAMP through interaction with AC.

Nevertheless these two pathways are not completely separate from the tran-scriptional route as PKA or cAMP might also influence cAMP response elements (CRE) and hence the transcription of genes.Another possible example of "crosstalk" is the stimulation of ER transcriptional activity by growth factors such as epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) [20].

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