DiurnalIn Vivoand RapidIn VitroEffects of Estradiol on Voltage-Gated Calcium Channels in Gonadotropin-Releasing Hormone Neurons

Abstract

A robust surge of gonadotropin-releasing hormone (GnRH) release triggers the luteinizing hormone surge that induces ovulation. The GnRH surge is attributable to estradiol feedback, but the mechanisms are incompletely understood. Voltage-gated calcium channels (VGCCs) regulate hormone release and neuronal excitability, and may be part of the surge-generating mechanism. We examined VGCCs of GnRH neurons in brain slices from a model exhibiting daily luteinizing hormone surges. Mice were ovariectomized (OVX), and a subset was treated with estradiol implants (OVXϩE). OVXϩE mice exhibit negative feedback in the A.M. and positive feedback in the P.M. GnRH neurons express prominent high-voltage-activated (HVA) and small low-voltage-activated (LVA) macroscopic (whole-cell) Ca currents (I Ca ). LVA-mediated currents were not altered by estradiol or time of day. In contrast, in OVXϩE mice, HVA-mediated currents varied with time of day; HVA currents in cells from OVXϩE mice were lower than those in cells from OVX mice in the A.M. but were higher in the P.M. These changes were attributable to diurnal alternations in L-and N-type components. There were no diurnal changes in any aspect of HVA-mediated I Ca in OVX mice. Acute in vitro treatment of cells from OVX and OVXϩE mice with estradiol rapidly increased HVA currents primarily through L-and R-type VGCCs by activating estrogen receptor ␤ and GPR30, respectively. These results suggest multiple mechanisms contribute to the overall feedback regulation of HVA-mediated I Ca by estradiol. In combination with changes in synaptic inputs to GnRH neurons, these intrinsic changes in GnRH neurons may play critical roles in estradiol feedback.

Voltage-Gated Potassium Currents Are Targets of Diurnal Changes in Estradiol Feedback Regulation and Kisspeptin Action on Gonadotropin-Releasing Hormone Neurons in Mice1

“…The lack of diurnal changes in potassium currents in GnRH neurons from OVX mice indicates these currents are altered as a result of interactions between estradiol and the circadian pacemaker. This observation is consistent with that from previous studies in this animal model in which no diurnal change in LH levels, GnRH neuron firing activity, fast synaptic transmission, or calcium currents were observed in GnRH neurons in cells from OVX mice in the absence of estradiol [10][11][12]. It is important to point out that other types of potassium currents, such as Mtype and inward rectifiers, may also be correlated with changes in GnRH neuron activity in this model [44,45].…”

“…At the time those studies were conducted, however, the daily surge was not appreciated in the OVXþE mouse, and hence, these important currents have not been studied in a model in which the timing of estradiol negative and positive feedback is well defined. Previous work in the daily surge model indicates that both intrinsic conductances of [10] and synaptic inputs to [11,12] GnRH neurons change with time of day, suggesting both of these mechanisms can contribute to the switch in estradiol feedback action. In contrast, some other intrinsic properties [13] are not altered by time of day, suggesting their primary controller is estradiol alone, without input from additional diurnal signals.…”

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

“…E2-driven modulation of voltage-gated Ca 2+ channel activity is also implicated in the regulation of hormone release and neuronal excitability in GnRH neurons (Zhang et al, 2009). Recent studies indicate that GPER1 may contribute to E2-mediated regulation of Ca 2+ signalling as the GPER1 agonist G1 mirrored the facilitation of Ca 2+ currents induced by E2 in GnRH neurons (Sun et al, 2010). In support of a role for GPER1, the ability of E2 to modulate Ca 2+ oscillations in primate GnRH neurons is mimicked by G1…”

Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: Insight from animal models

“…This suggests that androgens may have activational effects to increase synaptic contacts to GnRH neurons, in addition to possible organizational effects discussed in section 3.2.1. With regard to steroid modulation of intrinsic properties of GnRH neurons, a recent study examined voltage-gated calcium currents in GnRH neurons exposed in vivo to similar steroid milieu (Sun and Moenter, 2010). Voltage-gated calcium channels mediate neuronal influx of calcium, which governs cellular excitability and is critical for hormone release.…”

“…Steroids can also have rapid, non-genomic effects mediated by membrane receptors, and this was recently demonstrated in GnRH neurons. High physiological levels of estradiol were shown to directly activate GnRH neurons in mice and primates (Abe and Terasawa, 2005; Sun et al, 2010). In mice, this activation depends at least in part on reduction of calcium-activated potassium currents, increases in the sodium-current underlying the slow afterdepolarization, and increases in L- and R-type calcium currents (Sun et al, 2010).…”