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Abstract
The estrogen receptor and glucocorticoid receptor are members of the nuclear receptor superfamily that can signal using both non-genomic and genomic transcriptional modes. Though genomic modes of signaling have been well characterized and several behaviors attributed to this signaling mechanism, the physiological significance of non-genomic modes of signaling has not been well understood. This has partly been due to the controversy regarding the identity of the membrane ER (mER) or membrane GR (mGR) that may mediate rapid, non-genomic signaling and the downstream signaling cascades that may result as a consequence of steroid ligands binding the mER or the mGR. Both estrogens and glucocorticoids exert a number of actions on the hypothalamus, including feedback. This review focuses on the various candidates for the mER or mGR in the hypothalamus and the contribution of non-genomic signaling to classical hypothalamically driven behaviors and changes in neuronal morphology. It also attempts to categorize some of the possible functions of non-genomic signaling at both the cellular level and at the organismal level that are relevant for behavior, including some behaviors that are regulated by both estrogens and glucocorticoids in a potentially synergistic manner. Lastly, it attempts to show that steroid signaling via non-genomic modes may provide the organism with rapid behavioral responses to stimuli.
Highlights
GENOMIC AND NON-GENOMIC SIGNALING BY NUCLEAR RECEPTORS Nuclear receptor ligands such as estrogen and glucocorticoids signal via both non-genomic and genomic pathways within cells
Extracts from rat hippocampal synaptoneurosomes showed a reduction in Akt and ERK phosphorylation within 30 min in response to pharmacological inhibition of the glucocorticoid receptor (GR) by RU-486 [12], suggesting that the classical nuclear receptor was required for non-genomic signaling in the hippocampus
Apart from kinase activation, dexamethasone-mediated negative feedback at the corticotropin releasing hormone (CRH) neuron was rapid, consisting of suppression of the excitatory drive to the CRH neuron, mediated by endocannabinoids acting as a retrograde messenger to the presynaptic glutamatergic neuron [13], an effect mimicked with a membrane-limited dexamethasone conjugated to bovine serum albumin (Dex-BSA) [13]
Summary
Www.frontiersin.org treatment of hippocampal slices from female rats removed ERα from the synaptosomal plasma membrane by depalmitoylation within 20 min [37]. It is difficult to reconcile this with the increase in plasma mERα that is seen in the hypothalamic primary neuronal and astrocytic cultures [38, 39] and in the hypothalamic cell line mHypoE-38 [52] unless ERα from other non-membrane locations decrease to a large extent; this could be a parameter to be investigated in future studies. This could be due to the recent studies that show an increase ERα at the plasma membrane being carried out in primary cultures versus hypothalamic tissue that retain neuronal connectivity in the older studies. A 36 kDa variant lacking the AF-1 and AF-2 domains with a unique C-terminus was detected in human breast
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