17β-Estradiol Rapidly Increases KATP Activity in GnRH via a Protein Kinase Signaling Pathway

Abstract

17Beta-estradiol (E2) both inhibits and excites GnRH neurons via presynaptic as well as postsynaptic mechanisms. Although it has been demonstrated that E2 can alter the excitability of GnRH neurons via direct actions, the intracellular signaling cascades mediating these actions are not well understood. Previously we have shown that the activity of one of the critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state, the ATP-sensitive potassium channel (K(ATP)) channel, is augmented by E2 in ovariectomized females. However, the mRNA expression of the K(ATP) channel subunits Kir6.2 and SUR1 are unchanged with in vivo E2 treatment. Therefore, to elucidate the cellular signaling mechanism(s) modulating the channel activity, we did whole-cell patch-clamp recording of enhanced green fluorescent protein-GnRH neurons from ovariectomized female mice to study the acute effects of E2. E2 dose-dependently (EC(50) = 0.6 nM) enhanced the diazoxide (channel opener)-activated K(ATP) channel currents by 1.2- to 2.0-fold, which was antagonized by ICI 182,780. E2-BSA was equally as effective as E2, whereas 17 alpha-estradiol [corrected] had no effect. The protein kinase A (PKA) activator forskolin mimicked the effects of E2, whereas the PKA inhibitor H89 and the protein kinase C (PKC) inhibitor bisindolylmaleimide I blocked the effects of E2. Similar to E2, STX, a membrane estrogen receptor (ER) agonist that does not bind to ERalpha or ERbeta, also potentiated the diazoxide-induced K(ATP) channel current by 1.5-fold. Therefore, E2 can potentiate K(ATP) channel activity in GnRH neurons through a membrane ER-activated PKC-PKA signaling pathway.

Neuroprotective effects of 17β-estradiol associate with KATP in rat brain

“…Similar associations have been found between estrogen and K ATP channels in the neuroendocrine system [15,16]. Zhang et al [15] reported that 17b-estradiol could enhance K ATP channel activity in GnRH neurons through an ER-activated PKC-PKA signaling pathway. Neurons in the brain, like those of the myocardium, are excitable cells, and the K ATP channels can affect these neurons in similar ways.…”

“…It has also been reported that 17b-estradiol increased the levels of SUR2A mRNA, the regulatory subunit of the K ATP channel, in heart-derived H9c2 cells [14]. Similar associations have been found between estrogen and K ATP channels in the neuroendocrine system [15,16]. Zhang et al [15] reported that 17b-estradiol could enhance K ATP channel activity in GnRH neurons through an ER-activated PKC-PKA signaling pathway.…”

“…Our results are consistent with those of other studies in cardiac, pancreatic b-cells, and other tissues. Previous studies have found that estradiol increases K ATP channel activity in GnRH neurons through an ER-activated PKC-PKA signaling pathway [15]. Other investigators have reported that estradiol can regulate K ATP channel activity in pancreatic b-cells [22,23].…”

GnRH Neurons of Young and Aged Female Rhesus Monkeys Co-Express GPER but Are Unaffected by Long-Term Hormone Replacement

“…The lack of an obvious reproductive phenotype of the GPER-knockout mice may have hindered research in this area, as the global knockout may have developmental compensation for physiological roles normally mediated by GPER and, as discussed above, the role of GPER may be different in primates [18, 22, 59, 60]. There are still substantial gaps in knowledge about the receptors that mediate positive and negative effects of estrogens on GnRH neurons, making the GPER of potential interest beyond ERα, ERβ and STX-sensitive receptors [22, 57, 61].…”

“…Previously, E 2 regulation of GnRH cells was thought to be entirely indirectly mediated by other neuronal cell types and/or glia, because GnRH cells do not co-express estrogen receptor (ER) α [17]. GnRH cells are now known to contain ERβ, STX-sensitive estrogen receptors, and G protein-coupled membrane estrogen receptor (GPER, sometimes called GPR30) [18–23]. Of these, membrane ERs enable GnRH cells to respond rapidly to E 2 with increased action potential rate, intracellular Ca 2+ oscillations, and GnRH peptide release [23–27].…”