Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-α by IGF-1 in Hippocampus of Ovariectomized Rats

Abstract

In the absence of ovarian estrogens, increased levels of estrogen receptor (ER)α in the hippocampus are associated with improvements in cognition. In vitro evidence indicates that under conditions of low estrogen, growth factors, including Insulin-Like Growth Factor 1 (IGF-1), can activate ERα and regulate ERα-mediated transcription through mechanisms that likely involve modification of phosphorylation sites on the receptor. The goal of the current work was to investigate a role for IGF-1 in ligand-independent activation of ERα in the hippocampus of female rats. Ovariectomized rats received a single intracerebroventricular infusion of IGF-1 and hippocampi were collected 1 or 24 hours later. After 1 h, IGF-1 increased hippocampal levels of phosphorylated ERα at serine 118 (S118) as revealed by Western blotting. Coimmunoprecipitation revealed that at 1 hour after infusion, IGF-1 increased association between ERα and steroid receptor coactivator 1, a histone acetyltransferase that increases transcriptional activity of phosphorylated ERα. IGF-1 infusion increased levels of the ERα-regulated proteins ERα, choline acetyltransferase, and brain-derived neurotrophic factor in the hippocampus 24 hours after infusion. Results indicate that IGF-1 activates ERα in ligand-independent manner in the hippocampus via phosphorylation at S118 resulting in increased association of ERα with steroid receptor coactivator 1 and elevation of ER-regulated proteins. To our knowledge, these data are the first in vivo evidence of ligand-independent actions of ERα and provide a mechanism by which ERα can impact memory in the absence of ovarian estrogens.

Neuroestrogen-Dependent Transcriptional Activity in the Brains of ERE-Luciferase Reporter Mice following Short- and Long-Term Ovariectomy

“…Growth factors such as insulin-like growth factor-1 (IGF-1) can influence estrogen receptor-dependent transcription in a ligand-independent manner by activating signaling pathways that lead to phosphorylation of estrogen receptors (Smith, 1998). Estrogen receptors and IGF-1 receptors colocalize in cells in the female rodent brain (Cardona-Gómez et al, 2000), and the administration of IGF-1 to the brains of ovariectomized rats results in increased phosphorylation of estrogen receptor α at serine-118 (Grissom and Daniel, 2016). This ligand-independent mechanism is presumed to be independent not only from ovarian estrogens, but from neuroestrogens as well.…”

Nuclear estrogen receptor activation by insulin-like growth factor-1 in Neuro-2A neuroblastoma cells requires endogenous estrogen synthesis and is mediated by mutually repressive MAPK and PI3K cascades

“…2.1.6 Western Blotting-Western blotting was performed as described previously (Grissom & Daniel 2016) using 15ug of total protein from culture lysate. Separate blots were initially probed for either phospho-T202/Y204 p42/44 ERK (Cell Signaling 9101S; Danvers, MA) or phospho-serine 473 Akt (Cell Signaling 9271S).…”

“…We first found that increased levels of ERα in the hippocampus of ovariectomized rats enhances hippocampus-dependent memory (Rodgers et al 2010;Witty et al 2012), through a mechanism dependent on IGF-1R signaling (Witty et al 2013). We have also found that intrahippocampal infusion of IGF-1 increases phosphorylation of ERα at serine-118 and expression of estrogen receptor-dependent target genes (Grissom & Daniel 2016). We have separately shown that continuous, unopposed estradiol exposure enhances hippocampus-dependent memory in ovariectomized rats through a mechanism dependent on brain-derived estradiol (Nelson et al 2016).…”

Bilateral Ovariectomy Decreases the Levels of Cyclic Nucleotides and Nuclear Phosphorylated Estrogen Receptor-Alpha in Memory-Sensitive Rat Brain Regions

“…Most of these studies indicate cross-talk between peptide growth factor, insulin growth factor and neurotransmitters such as dopamine through kinase activity, not through increasing the level of cyclic nucleotides. 12,[36][37][38] Moreover, it has been documented that cyclic nucleotides promote the phosphorylation of ERα in brain tissues suggesting that cyclic nucleotides are important mediators in the mechanism of estrogen through ERα receptor activity. 38,39 Our present study reports that there was a significant loss in the level of cyclic nucleotides such as cAMP and cGMP in all memory-sensitive brain regions of ovariectomized rodents.…”