Abstract
Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17β-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues.
Highlights
The local conversion of androgens into estrogens in specific areas of the central nervous system is an essential step in the activation of numerous testosterone-dependent physiological and behavioral processes, including sexual differentiation of the brain, negative feedback on the secretion of gonadotrophin releasing hormone and the activation of male sexual and aggressive behaviors (Beyer et al, 1976; MacLusky and Naftolin, 1981; Bagatell et al, 1994; Fisher et al, 1998; Honda et al, 1998; Toda et al, 2001; Rochira et al, 2006; Trainor et al, 2006)
We further investigated whether the rapid inhibition of aromatase activity (AA) by ATP/Mg/Ca-dependent phosphorylation processes is specific to the neuronal environment or can be observed in other aromatase-rich tissues
A few laboratories have accumulated strong evidence showing that AA can be rapidly modulated via posttranslational modifications, most notably via phosphorylation
Summary
The local conversion of androgens into estrogens in specific areas of the central nervous system is an essential step in the activation of numerous testosterone-dependent physiological and behavioral processes, including sexual differentiation of the brain, negative feedback on the secretion of gonadotrophin releasing hormone and the activation of male sexual and aggressive behaviors (Beyer et al, 1976; MacLusky and Naftolin, 1981; Bagatell et al, 1994; Fisher et al, 1998; Honda et al, 1998; Toda et al, 2001; Rochira et al, 2006; Trainor et al, 2006). An acute estrogenic treatment in vitro triggers the activation of numerous intracellular signaling pathways including phosphorylation of the mitogen-activated protein kinase (MAPK) and cAMP response element binding protein (CREB) and changes in intracellular calcium concentrations (Mermelstein et al, 1996; Moss et al, 1997; Kenealy et al, 2011; Roepke et al, 2005) In the brain, these modifications lead to modulations of neuronal activity (Joels, 1997; Moss et al, 1997; Rønnekleiv and Kelly, 2002; Abraham et al, 2003, 2004; Boulware et al, 2005) and can in some instance rapidly affect behavior in numerous species (Hayden-Hixson and Ferris, 1991; RemageHealey and Bass, 2004; Dewing et al, 2007; Micevych and Mermelstein, 2008; Lord et al, 2009; Seredynski et al, 2013; see Cornil et al, 2012a for review). The rapid effects of E2 introduced above require mechanisms affecting the synthesis of the steroid more rapidly, suggesting posttranslational change(s) of the protein activity
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