Steroid receptor coactivator-2 expression in brain and physical associations with steroid receptors

Abstract

Estradiol and progesterone bind to their respective receptors in the hypothalamus and hippocampus to influence a variety of behavioral and physiological functions, including reproduction and cognition. Work from our lab and others has shown that the nuclear receptor coactivators, steroid receptor coactivator-1 (SRC-1) and SRC-2, are essential for efficient estrogen receptor (ER) and progestin receptor (PR) transcriptional activity in brain and for hormone-dependent behaviors. While the expression of SRC-1 in brain has been studied extensively, little is known about the expression of SRC-2 in brain. In the present studies, we found that SRC-2 was highly expressed throughout the hippocampus, amygdala and hypothalamus, including the medial preoptic area (MPOA), ventral medial nucleus (VMN), arcuate nucleus (ARC), bed nucleus of the stria terminalis, supraoptic nucleus and suprachiasmatic nucleus. In order for coactivators to function with steroid receptors, they must be expressed in the same cells. Indeed, SRC-2 and ERα were coexpressed in many cells in the MPOA, VMN and ARC, all brain regions known to be involved in female reproductive behavior and physiology. While in vitro studies indicate that SRC-2 physically associates with ER and PR, very little is known about receptor-coactivator interactions in brain. Therefore, we used pull-down assays to test the hypotheses that SRC-2 from hypothalamic and hippocampal tissue physically associate with ER and PR subtypes in a ligand-dependent manner. SRC-2 from both brain regions interacted with ERα bound to agonist, but not in the absence of ligand or in the presence of the selective ER modulator, tamoxifen. Analysis by mass spectrometry confirmed these ligand-dependent interactions between ERα and SRC-2 from brain. In dramatic contrast, SRC-2 from brain showed little to no interaction with ERβ. Interestingly, SRC-2 from both brain regions interacted with PR-B, but not PR-A, in a ligand-dependent manner. Taken together, these findings reveal that SRC-2 is expressed in brain regions known to mediate a variety of steroid-dependent functions. Furthermore, SRC-2 is expressed in many ERα containing cells in the hypothalamus. Finally, SRC-2 from brain interacts with ER and PR in a subtype-specific manner, which may contribute to the functional differences of these steroid receptor subtypes in brain.

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…Thus, the latter dose was used in further experiments. Incidentally, it should be noted that concentrations in the high-nM range have been largely used to investigate gene transcriptional regulation by E 2 [23][24][25][26][27] or metabolic effect of this hormone [28]. Moreover, it has been shown that intratesticular concentrations are much higher than serum levels of E 2 [29].…”

Nuclear Receptor Coactivators Are Coexpressed with Steroid Receptors and Regulated by Estradiol in Mouse Brain

“…In support of this idea, ER and other steroid receptors have distinct affinities for nuclear receptor coactivators. For example, SRC-1 and SRC-2 from the rat hypothalamus and hippocampus physically associate with ER and PR in a receptor subtype- and brain region-specific manner [58,65]. Interestingly, SRC-1 from the hypothalamus interacts more with ERα than ERβ, while SRC-2 associates with ERα but shows virtually no interaction with ERβ [58,65].…”

“…For example, SRC-1 and SRC-2 from the rat hypothalamus and hippocampus physically associate with ER and PR in a receptor subtype- and brain region-specific manner [58,65]. Interestingly, SRC-1 from the hypothalamus interacts more with ERα than ERβ, while SRC-2 associates with ERα but shows virtually no interaction with ERβ [58,65]. In addition, receptor-coactivator interactions are influenced by different ligands and response elements on DNA [90,91,92,93].…”

“…Recent work reveals that two members of this p160 family of coactivators, SRC-1 and SRC-2, are important for hormone action in brain and behavior [46,47]. SRC-1 [48,49,50,51,52,53,54,55,56,57] and SRC-2 [58,59,60] are expressed at high levels in the cortex, hypothalamus and hippocampus of rodents. Our laboratory and others have found that SRC-1 and SRC-2 are important for hormone-dependent sexual differentiation of the brain [53], gene expression in brain [54,61,62,63] and sexual behavior [54,61,62,63,64].…”

“…Our laboratory and others have found that SRC-1 and SRC-2 are important for hormone-dependent sexual differentiation of the brain [53], gene expression in brain [54,61,62,63] and sexual behavior [54,61,62,63,64]. Finally, SRC-1 and SRC-2 from rodent brain physically interact with ER and PR in a receptor subtype- and brain region-specific manner [58,65]. …”