title: Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives.
abstract: Estrogens play a critical role in many aspects of physiology, particularly female reproductive function, but also in pathophysiology, and are associated with protection from numerous diseases in premenopausal women. Steroids and the effects of estrogen have been known for ∼90 years, with the first evidence for a receptor for estrogen presented ∼50 years ago. The original ancestral steroid receptor, extending back into evolution more than 500 million years, was likely an estrogen receptor, whereas G protein-coupled receptors (GPCRs) trace their origins back into history more than one billion years. The classical estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that confer estrogen sensitivity upon many genes. It was soon apparent that these, or novel receptors may also be responsible for the "rapid"/"non-genomic" membrane-associated effects of estrogen. The identification of an orphan GPCR (GPR30, published in 1996) opened a new field of research with the description in 2000 that GPR30 expression is required for rapid estrogen signaling. In 2005-2006, the field was greatly stimulated by two studies that described the binding of estrogen to GPR30-expressing cell membranes, followed by the identification of a GPR30-selective agonist (that lacked binding and activity towards ERα and ERβ). Renamed GPER (G protein-coupled estrogen receptor) by IUPHAR in 2007, the total number of articles in PubMed related to this receptor recently surpassed 1000. In this article, the authors present personal perspectives on how they became involved in the discovery and/or advancement of GPER research. These areas include non-genomic effects on vascular tone, receptor cloning, molecular and cellular biology, signal transduction mechanisms and pharmacology of GPER, highlighting the roles of GPER and GPER-selective compounds in diseases such as obesity, diabetes, and cancer and the obligatory role of GPER in propagating cardiovascular aging, arterial hypertension and heart failure through the stimulation of Nox expression.
authors.affiliation: Molecular Internal Medicine, University of Zürich, 8057 Zürich, Switzerland. Electronic address: barton@access.uzh.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.affiliation: Rhode Island Hospital, Brown University, Providence, RI 02903, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Filardo
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lolait
authors.affiliation: Marine Science Institute, University of Texas at Austin, Port Aransas, TX 78373, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center and University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131, USA. Electronic address: eprossnitz@salud.unm.edu.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
mesh_terms: D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: Adolf Butenand; Adolf Windaus; Charles-Édouard Brown-Séquard; Clara Szego; Edward Doisy; Estrogen; Ferdinand Mainzer; GPCR; History; IUPHAR; Non-genomic; Pathology; Pathophysiology; Physiology; Rudolf Chrobak