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, 22 (10), 2250-9

Converse Regulatory Functions of Estrogen Receptor-Alpha and -Beta Subtypes Expressed in Hypothalamic Gonadotropin-Releasing Hormone Neurons

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Converse Regulatory Functions of Estrogen Receptor-Alpha and -Beta Subtypes Expressed in Hypothalamic Gonadotropin-Releasing Hormone Neurons

Lian Hu et al. Mol Endocrinol.

Erratum in

  • Mol Endocrinol. 2009 Mar;23(3):423

Abstract

Estradiol (E(2)) acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion. However, the extent to which these actions are mediated by estrogen receptors (ERs) expressed in GnRH neurons has been controversial. In this study, Single-cell RT-PCR revealed the expression of both ERalpha and ERbeta isoforms in cultured fetal and adult rat hypothalamic GnRH neurons. Both ERalpha and ERbeta or individual ERs were expressed in 94% of cultured fetal GnRH neurons. In adult female rats at diestrus, 68% of GnRH neurons expressed ERs, followed by 54% in estrus and 19% in proestrus. Expression of individual ERs was found in 24% of adult male GnRH neurons. ERalpha exerted marked G(i)-mediated inhibitory effects on spontaneous action potential (AP) firing, cAMP production, and pulsatile GnRH secretion, indicating its capacity for negative regulation of GnRH neuronal function. In contrast, increased E(2) concentration and ERbeta agonists increase the rate of AP firing, GnRH secretion, and cAMP production, consistent with ERbeta-dependent positive regulation of GnRH secretion. Consonant with the coupling of ERalpha to pertussis toxin-sensitive G(i/o) proteins, E(2) also activates G protein-activated inwardly rectifying potassium channels, decreasing membrane excitability and slowing the firing of spontaneous APs in hypothalamic GnRH neurons. These findings demonstrate that the dual actions of E(2) on GnRH neuronal membrane excitability, cAMP production, and GnRH secretion are mediated by the dose-dependent activation of ERalpha and ERbeta expressed in hypothalamic GnRH neurons.

Figures

Figure 1
Figure 1
Expression of ERα and ERβ in Rat Hypothalamic GnRH Neurons A, Single-cell RT-PCR of individual fetal and adult rat GnRH neurons showing amplicons for GnRH, ERα, and ERβ (sample 1–sample 7), positive and negative controls, and ladder marker. B, Histograms showing the frequency of detection of GnRH + ERα, and ERβ, GnRH + ERα, GnRH + ERβ, and GnRH alone transcripts in cultured fetal GnRH neurons, C, Adult female rats. D, Adult male rats. Cont., Control; Neg., negative control.
Figure 2
Figure 2
Spontaneous Electrical Activity and E2-Induced Activation of GIRK Current in Identified GnRH Neurons A, Inhibition of AP firing during E2 treatment and reversal of the inhibitory action and transition to the stimulatory action of E2 on AP firing during treatment with an ERα antagonist. B, Stimulation of AP firing by E2 and transition to the stimulatory action of E2 on AP firing during treatment with an ERα antagonist. C, Inhibition of AP firing by ERα agonist and recovery of AP firing during washout period. D, ERβ agonist-induced increase in spontaneous AP firing in cultured hypothalamic GnRH neurons and recovery of AP firing during washout period. Ag., Agonist; Ant., antagonist.
Figure 3
Figure 3
E2-Induced Activation of GIRK Current in Identified GnRH Neurons A, E2-induced potentiation of GIRK current (open circles) and pertussis toxin-induced inhibition of E2-activated GIRK current (triangles). B, Current-voltage relationships of basal GIRK current (open squares), E2-activated (open circles), and pertussis toxin-induced inhibition of E2-activated GIRK current (open triangles). ms, Millisecond.
Figure 4
Figure 4
Effects of ER Subtypes on cAMP Production in GT1–7 Cells A, Biphasic dose-dependent cAMP responses to E2 (open circles) were inhibited by pretreatment with the ER antagonist, ICI 182,780 (open squares). B, Concentration-dependent inhibition and stimulation of cAMP by E2 in GT1–7 cells (open circles). An inhibitory action of E2 on cAMP production was prevented, and stimulatory action potentiated, in presence of selective ERα antagonist (solid circles). C, Stimulatory action of E2 on cAMP production was prevented, and inhibitory action unaltered in presence of ERβ antagonist (closed circles). D, Inhibition of cAMP production by a selective ERα agonist (open circles) and its reversal by an ERα antagonist in GT1–7 cells (solid circles). E, Stimulation of cAMP production by a selective ERβ agonist (open circles), and its reversal by an ERβ antagonist in GT1–7 cells (solid circles). E2 and ER agonist and antagonist analogs were applied in equimolar concentrations. Data are means ± ses of four experiments. Single asterisks indicate a significant difference compared with the control. Double asterisks indicate significant difference between control and treated groups. Ag, Agonist; Ant, antagonist; ICI, ICI 182,780.
Figure 5
Figure 5
Neurosecretory Actions of E2 in Perifused GT1–7 Cells A, Basal pulsatile GnRH release from perifused GT1–7 cells. B, E2-induced transient stimulation and prolonged inhibition of pulsatile GnRH secretion. C, Inhibition of pulsatile GnRH release by a selective ERα agonist. D, Stimulation of pulsatile GnRH release by a selective ERβ agonist. Representative traces of four independent experiments are shown, and detected GnRH pulses are indicated by asterisks. Ag, Agonist.

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