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Review
. 2015 Feb 16:6:18.
doi: 10.3389/fendo.2015.00018. eCollection 2015.

Membrane-initiated non-genomic signaling by estrogens in the hypothalamus: cross-talk with glucocorticoids with implications for behavior

Jennifer Rainville  1 , Kevin Pollard  2 , Nandini Vasudevan  3
Affiliations
Review

Membrane-initiated non-genomic signaling by estrogens in the hypothalamus: cross-talk with glucocorticoids with implications for behavior

Jennifer Rainville et al. Front Endocrinol (Lausanne). .

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.

Keywords: GPCR; aggression; estrogen receptor variants; glucocorticoid receptor; hypothalamus; lordosis; membrane-initiated signaling; spine density.

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Figures

Figure 1
Figure 1
Domain structure of the ERα and the GRα. ERα and GRα are classical intracellular nuclear receptors but may also be present on the plasma membrane. Both receptors have a N-terminal AF-1 domain, a central DNA binding domain, a hinge domain (H), and a C-terminal AF-2 domain, required to bind ligand. ERα: the antibodies most commonly used to detect ERα are the H184 (Santa Cruz Biotechnology, TX, USA) antibody raised to the N-terminal domain and the MC-20 (Santa Cruz Biotechnology, TX, USA) and C1335 (Upstate Biotechnology, NY, USA) raised to the C-terminal domain. In addition, the sites that may tether the ERα to the plasma membrane are marked. These are residues required for caveolin or Gαi binding or residues that are palmitoylated or required for dimerization at the membrane. GRα: the antibodies most commonly used to detect GRα are the BuGR antibody (Abcam Inc., MA, USA) and the M-20 (Santa Cruz Biotechnology, TX, USA) antibody, directed to the N-terminal domain. The NLS refers to the nuclear localization signal since nuclear localization of this receptor can occur rapidly and is a non-genomic effect.
Figure 2
Figure 2
Hypothetical model in the rodent for the rapid and sustained increase in aggression that is seen when an intruder enters a resident’s home-cage. On visual and/or olfactory cues, 17β-E in the brain may increase corticosterone via an unknown mechanism. This increase in corticosterone may rapidly and non-genomically increase aggressive behavior. The mechanism by which corticosterone does so is not known but may involve the regulation of aromatase and could be GR mediated. It is not known if 17β-E’s regulation of aggressive behavior is solely via corticosterone increase or these are two parallel pathways, which require ERα, as shown in the figure. Elevated corticosterone levels can increase transcription from the brain-specific aromatase promoter, which in turn increases neuroestrogens. This may contribute to shorter latencies of attack in successive bouts. The interaction of estrogen and corticosterone ensures that the resident rodent is aggressive only in the presence of a relevant external cue, i.e., intruder and a relevant internal cue, i.e., sufficient 17β-E.
Figure 3
Figure 3
Priming of transcription within neurons by non-genomic signaling. Non-genomic signaling, initiated at the plasma membrane by an unknown mER can activate ERK signaling, which in turn may cause phosphorylation of the ERα and increased transcription from promoters than contain EREs (130). Alternatively, ERK signaling may also lead via unknown mechanisms to increased transcription from the c-Fos promoter (190) while PKA signaling generated by the mER may lead to increased transcription from promoters that have a cAMP response element (CRE) enhancer (189).
Figure 4
Figure 4
Functions of non-genomic signaling initiated by the mER or the mGR in the CNS. Both mER and mGR contribute to the regulation of male territorial aggression and spinogenesis in neurons, as well as synergizing with other rapid signaling pathways. In the pre-opiomelanocortin (POMC) neuron shown on the left, non-genomic signaling by the mER increases neuronal excitability while rapid negative feedback by the mGR in corticotropin releasing hormone (CRH) neurons decreases neuronal excitability (shown on the right). In addition, the mER plays a role in male sexual behavior and may interact with GPR30 regulates lordosis behavior in female rodents. Glucocorticoids via the mGR also increase neuroestrogen concentrations, via aromatase activity and the increase in aromatase protein, thus providing a route by which the actions of estrogens and glucocorticoids can converge in the brain.
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