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

Abstract

Keywords: G protein coupled estrogen receptor, hippocampal synaptic function; receptor trafficking; learning and memory; neuroprotection; synaptic plasticity. Estrogens play a key role in regulating reproductive and neuroendocrine function by activating classical nuclear steroid receptors that act as ligand gated transcription factors.However evidence is growing that estrogens also promote rapid non-genomic responses via activation of membrane-associated estrogen receptors. The G protein-coupled estrogen receptor (GPER1; also known as GPR30) has been identified as one of the main estrogensensitive receptors responsible for the rapid non-genomic actions of estrogen. In recent years, our understanding of the CNS actions of GPER1s has significantly increased following the development of selective pharmacological tools and via the use of transgenic technologies to knockout GPER1 in mice. Here we review recent advances that have been made to uncover the role of GPER1s in the CNS.Introduction.

The G protein‐coupled oestrogen receptor, GPER1, mediates direct anti‐inflammatory effects of oestrogens in human cholinergic neurones from the nucleus basalis of Meynert

“…It is well documented that the central effects of E 2 are mediated by the classical oestrogen receptors (ERs), ERα and ERβ, which function as transcription factors that are able to regulate the activity of different genes, as well as by the membrane‐bound G protein‐coupled oestrogen receptor GPER1 (also called GPR30), which mediates rapid non‐genomic effects . Increasing evidence supports a major role for GPER1 with respect to mediating the neuroprotective effects of oestrogens on the main cognitively relevant brain structures . All types of oestrogen receptors have been localised in multiple brain areas and are expressed in varying densities in both sexes .…”

“…24 Increasing evidence supports a major role for GPER1 with respect to mediating the neuroprotective effects of oestrogens on the main cognitively relevant brain structures. 25 All types of oestrogen receptors have been localised in multiple brain areas and are expressed in varying densities in both sexes. 26,27 However, it has been suggested that GPER1 activation may be particularly involved in mediating the positive effects of E 2 on cognitive performance at the level of cholinergic afferents innervating the hippocampus and cortex, 28,29 thereby directly acting on hippocampal synaptic function.…”

Evaluation of estrogen and G protein-coupled estrogen receptor 1 (GPER) levels in drug-naïve patients with attention deficit hyperactivity disorder (ADHD)

“…Estrogen is the primary female sex hormone with a crucial role in the regulation of reproductive and neuroendocrine function. Different studies reported that estrogen also modulates synaptic plasticity in the hippocampus, regulates the formation of amyloid-β peptide, inactivates the expression of proapoptotic factors, and demonstrates antioxidant activity [8].…”

Sex Hormones and Alzheimer’s Disease

“…The nuclear ER are either ERα or ERβ, which are responsible for the estrogen genomic action through regulation of various transcriptional gene expression mechanisms. The brain contains both types of nuclear ER, which are abundant in the hippocampus, pyramidal cells and glial tissue [42]. The membrane estrogen receptors (mERs) are G protein-coupled and ligand-gated ion channels, including GPER1 (previously known as GPR30), ER-X and Gq-mER, which are responsible for the rapid nongenomic actions of estrogen that is initiated within minutes after estrogen administration (estrogen neurotransmitter actions) due to recruitment and activation of kinase-dependent signaling pathways.…”