Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival

Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein–Coupled Estrogen Receptor in Pancreatic Islet Survival Suhuan Liu 1 , Cedric Le May 1 , Winifred P.S. Wong 1 , Robert D. Ward 2 , Deborah J. Clegg 3 , Marco Marcelli 2 , Kenneth S. Korach 4 and Franck Mauvais-Jarvis 1 1 Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, Illinois; 2 Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston, Texas; 3 Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas; 4 National Institutes of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. Corresponding author: Franck Mauvais-Jarvis, f-mauvais-jarvis{at}northwestern.edu . Abstract OBJECTIVE We showed that 17β-estradiol (E 2 ) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E 2 activates nuclear estrogen receptors via an estrogen response element (ERE). E 2 also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival. RESEARCH DESIGN AND METHODS We used mice and islets deficient in estrogen receptor-α (αERKO −/− ), estrogen receptor-β (βERKO −/− ), estrogen receptor-α and estrogen receptor-β (αβERKO −/− ), and GPER (GPERKO −/− ); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes. RESULTS We show that ERα protection of islet survival is ERE independent and that E 2 favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO −/− mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO −/− mice and their islets, E 2 partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E 2 protection of islet survival is reproduced by a membrane-impermeant E 2 formulation and a selective GPER agonist. Accordingly, GPERKO −/− mice are susceptible to streptozotocin-induced insulin deficiency. CONCLUSIONS E 2 protects β-c