GPR30: Another Possible Drug Target
“For many years, steroids and estrogens were thought to function solely through nuclear hormone receptors,” said Eric Prossnitz, professor of cell biology and physiology at the University of New Mexico. “More recently, evidence has accumulated that GPCRs might also be involved in steroid signaling, especially for estrogen, and it has been suggested that GPR30 might mediate certain cellular responses.”
The novel G protein-coupled estrogen receptor GPR30 is a classic 7-transmembrane domain GPCR that, unlike most GPCRs, resides predominantly in the endoplasmic reticulum. From this location, it binds estrogen and activates numerous cellular-signaling pathways including calcium mobilization and PI3K activation.
“Although classical estrogen receptors can activate many of the same cellular effectors as GPR30,” Prossnitz said, “the signaling pathways differ for the two receptors. To quantitate and localize estrogen binding, we have developed a novel fluorescent estrogen analog that localizes with both classical estrogen receptors and GPR30.”
Consequently, GPR30 is gaining recognition as a potential target for the treatment of estrogen-dependent diseases. “The challenge, though, is that GPR30 binds to both agonists and antagonists of the classical nuclear estrogen receptors,” said Prossnitz. “You have to be able to investigate the individual functions of each receptor to understand their biology.”
Through virtual screening, a group of New Mexico scientists, led by Prossnitz, identified a high-affinity agonist for GPR30 that shows no significant binding to classical estrogen receptors. “The first paper we published showed that GPR30 could bind to estrogen-like compounds,” Prossnitz said. “Our more recent work has focused on the characterization of novel ligands that bind exclusively to either GPR30 or the classical estrogen receptors.”
Having identified a GPR30-specific agonist, Prossnitz and his group are beginning to evaluate the physiological functions of GPR30. “At this point, it is unclear what the pharmaceutical market for GPR30-targeted drugs might be, but we believe current and future work will show GPR30 to be involved in numerous physiological processes important to disease,” he concluded.