In this fashion, reproductive steroids were found

to regulate the expression of a variety of proteins of relevance for neural function (eg, neurotransmitter synthetic and metabolic enzymes, neuropeptides, receptors, etc). More recently, advances in neuroscience (reviewed in the accompanying article by McHwen8) have demonstrated vastly more complex, broad-ranging, and powerful mechanisms for neural control by reproductive steroids, and have further uncovered several regulatory principles that help explain how a given Inhibitors,research,lifescience,medical steroid signal may elicit diverse behavioral responses. One inescapable, overarching selleckchem principle is that the molecular and behavioral effects of steroids are highly context-dependent.

Cellular context Data overwhelmingly suggest that the cell is a context that determines the Inhibitors,research,lifescience,medical response to a stimulus. First, steroidactivated receptors influence transcription not as solitary agents, but by forming combinations with other intracellular proteins.9 Some of these proteins, the coregulators, determine whether gene transcription is enhanced or suppressed by the activated receptor. Other proteins, the cointegrators, permit activated receptors to regulate genomic expression through sites (eg, activator protein, Inhibitors,research,lifescience,medical API) other than the classical DNA hormone response elements, thus expanding the range of genes influenced by steroids.10 Many of these proteins are tissue specific, thus helping to explain how ER modulators (eg, tamoxifen and raloxifene) can act like agonists in some tissues Inhibitors,research,lifescience,medical (eg, bone) and like antagonists in other tissues (eg, breast).11,12 Second, different subtypes of the steroid receptors are either coded for on different genes (eg, estrogen receptors Inhibitors,research,lifescience,medical alpha and beta)13 or modified after transcription (eg, splice variants or progesterone receptor isoforms A and B).14 These subtypes have different distribution patterns in the brain, different affinities for ligands, and very different actions (including inhibition of the actions MRIP of other subtypes).15,16

Third, the relatively slow, “genomic” effects of reproductive steroids have been expanded in two dimensions: time, with a variety of rapid (seconds to minutes) “nongenomic” effects observed; and targets, which now include ion channels and second messengers. Once again, the effect observed depends upon the type of cell examined: estradiol activates the second messenger, mitogen-activated protein kinase (MAPK), in neurons, but decreases MAPK activation in cortical glia.17 Metabolic context As steroid hormones are highly homologous and serve as precursors for one another, the manner in which steroids are metabolized can markedly change the amplitude or nature of the steroid signal.