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Understanding the Role of the G Protein‐Coupled Estrogen Receptor (GPR30/GPER‐1) in Neurodevelopment

Several studies have commented on the effects of 17β‐estradiol(E2) on neurodevelopment. These studies have primarily focused on the classical nuclear estrogen receptors, ERα and ERβ. It has been established that E2 has the ability to activate rapid, non‐genomic signaling through the G Protein‐Coupled Estrogen Receptor (GPR30/GPER‐1). Few studies have examined the neurodevelopmental effects of selectively targeting GPER‐1. Previously, our group synthesized novel, selective GPER‐1 agonists. During biological evaluation, the pharmacology associated with the novel agonists appeared to differ from known GPER‐1 agonist, G‐1. Treatment with the beta‐gamma subunit inhibitor, galein, revealed a significant attenuation in signal for the synthesized agonists but not for G‐1 at concentrations above 1μM. Additionally, the efficacy of eliciting neurite outgrowth in rat hippocampal E18 neurons was greater for the synthesized agonists than G‐1. To further understand the observed differences in signaling between the synthesized compounds and G‐1, rat hippocampal E18 neurons and neural progenitor cells (NPCs) originating from healthy humans were studied. RNA sequencing was utilized to reveal the presence of changes in gene expression in response to GPER‐1 compounds in rat hippocampal E18 neurons, excitatory NPCs, and inhibitory NPCs. These results provide information regarding opportunities associated with targeting GPER‐1 in neurodevelopment as well as information related to the cell‐signaling pathway that may be leveraged in the design of new therapeutic lead compounds.