Estrogen modulation of hypothalamic neurons: Activation of multiple signaling pathways and gene expression changes
Introduction
It is evident that the gonadal steroid hormone estrogen (17β-estradiol, E2) imparts a multifaceted influence over synaptic transmission in the mammalian central nervous system. Not only can E2 alter synaptic responses via genomic mechanisms, but there exists a wealth of information that indicates the steroid can also modulate cell-to-cell communication much more rapidly (for review see [1]). These synaptic alterations are brought about via changes in the cellular responsiveness to the activation of various receptor systems (both G protein-coupled and ionotropic) to their respective first messengers. For example, E2 can modulate the cellular responsiveness to ionotropic glutamate (both N-methyl-d-aspartate (NMDA) and non-NMDA) receptor activation [2], [3], [4]. In addition, it can alter the linkage of G protein-coupled receptors such as opioid (both μ and κ), γ-aminobutyric acid (GABA)B and dopamine D2 receptors to their respective effector systems [5], [6], [7], [8], [9]. More recently, it appears that the steroid can function as a first messenger by activating an estrogen receptor that couples directly to K+ and Ca2+ channels by way of a pertussis toxin-sensitive G protein [10], [11]. While a clearer picture of the rapid signaling actions by estrogen is emerging, it is well established that E2 modulates neurotransmission via genomic mechanisms. This well characterized mechanism of transactivation involves ligand binding, nuclear receptor dimerization and binding to consensus estrogen response elements (EREs) [12]. The picture however is more complicated since there are at least two estrogen receptors (ERα and ERβ) that can homodimerize or heterodimerize, sequester other DNA-binding proteins, and enable transcription by response elements other than EREs, e.g., AP-1 and CREB sites (reviewed in [13], [14], [15]). Although a number of transcripts that are regulated by E2 have been identified [16], the full scope of estrogen's action is not known. Therefore, new approaches such as differential display and gene microarray [17], [18] are being used in order to ascertain a more global picture of E2-regulated genes and how these changes subsequently affect complex physiological processes such as reproduction, stress responses, feeding and cognition. We will focus on the integration of estrogen's rapid signaling to modulate channel activity with a particular focus on K+ channel activity as well as gene regulation in hypothalamic neurons that mediate many of these physiological processes.
Section snippets
Estrogen modulation of G protein-coupled inwardly rectifying K+ (GIRK) channels
One of the principal actions of estrogen is to regulate the output of gonadotropin-releasing hormone (GnRH) from the mediobasal hypothalamus and hence the reproductive cycle. Although we demonstrated direct actions of estrogen to inhibit GnRH neuronal activity over 15 years ago [10], [19], it has been only recently that estrogen receptors is identified in GnRH neurons [20], [21], [22]. Our studies using the in vitro slice preparation have revealed that μ-opioid receptor-mediated inhibition of
Cellular mechanisms of estrogen's rapid actions: activation of protein kinases
What is the underlying cause of estrogen-induced decrease in the responsiveness of hypothalamic neurons to the μ-opioid and GABAB receptor-mediated activation of GIRK channels? One insight comes from studies in which E2 has been shown to rapidly stimulate PKA activity in peripheral (e.g., uterine) tissue, as well as to stimulate cyclic adenosine monophosphate responsive element binding protein (CREB) and c-fos expression [63], [64], [65], [66], [67]. Furthermore, PKA activators such as Sp-cAMP
Estrogen modulation of hypothalamic neuronal activity via transcriptional regulation
As mentioned earlier, acute E2 exposure desensitizes μ-opioid- and GABAB receptor-mediated responses in POMC and dopamine neurons and that this negative modulatory effect of estrogen persists for at least 24 h following systemic steroid administration. How might the resulting increased firing of these neurons be sustained over time? Using an animal model we developed to study estrogen's feedback actions on secretion of gonadotropin-releasing hormone (GnRH) [47], we studied the transcriptional
Significance
Estrogen modulates the excitability of a number of neurons that are involved in the control of homeostasis, including reproduction, stress responses, feeding and motivated behaviors. Recently, we have gained some insight into the cellular and genomic mechanisms by which estrogen exerts its effects on these neurons. First of all, estrogen negatively modulates the coupling of the μ-opioid and/or GABAB receptors to their effector K+ channel in β-endorphin, dopamine and GABAergic neurons. This
Acknowledgements
The authors’ work was supported by PHS grants NS43330, NS38809, Training grant T-32 HD07133 and the Medical Research Foundation of Oregon.
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2014, General and Comparative EndocrinologyCitation Excerpt :However, many studies have reported increased ERα expression concomitant with increased vitellogenin expression after exposure to exogenous E2, while expression of ERβ subtypes decrease or exhibit no change [reviewed in Nelson and Habibi (2013)]. Moreover, many studies report cross-talk between estrogen-mediated pathways and other physiological systems (i.e. detoxification pathways and other endocrine axes (e.g. thyroid, stress and somatotropic axis)) (Lackey et al., 2001; Malyala et al., 2005; Tilghman et al., 2010; Vasudevan et al., 2002; Wang and Kilgore, 2002), however these interactions at the cellular and whole organism level have yet to be fully elucidated. Consequently, ongoing studies examining the molecular mechanism(s) of E2 action that underlie whole organism-level effects are necessary to comprehensively understand the complexity and wide-ranging effects of E2.