G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications

Abstract

The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.

Keywords: cancer; cardiovascular; endocrine; estrogen; immunity; metabolism.

Figure 1

Steroidal ligands of GPER. Abbreviations: ER, estrogen receptor; GPER, G protein–coupled estrogen receptor; PROTAC, proteolysis-targeting chimera; SERD, selective estrogen receptor downregulator/degrader.

Figure 2

Xenoestrogen ligands of G protein–coupled estrogen receptor (GPER).

Figure 3

Synthetic heterocycles with selectivity for GPER. Abbreviations: ER, estrogen receptor; GPER, G protein–coupled estrogen receptor; SERM, selective estrogen receptor modulator.

Figure 4

Examples of physiological effects resulting from selective GPER agonism. Abbreviations: CNS, central nervous system; GPER, G protein–coupled estrogen receptor.