“…These differential activities were subsequently understood at least in part at the molecular level based on the stabilization of distinct ER conformations (involving helix 12 of the ligand binding domain), which in turn result in differential recruiting of transcriptional coactivators and corepressors (Smith and O'Malley, 2004), in a ligand-and tissue-dependent manner (McDonnell and Wardell, 2010;Burris et al, 2013). Far less is understood regarding the mechanisms and pharmacology of rapid signaling via ERa and ERb (Banerjee et al, 2014), including their many splice variants (Kim et al, 2011;Chaudhri et al, 2014), and in particular, the agonistic rapid cellular effects of SERMs and SERDs, which can now at least be partially understood through their actions on GPER. However, just as our understanding of the actions of agonists, SERMs and SERDs for ERs has expanded over the years, GPCRs are now understood to exist in a number of activated conformations (Katritch et al, 2013), stabilized to varying extents by different ligands, that induce distinct subsets of downstream signaling pathways, processes termed functional selectivity or biased agonism (Kenakin, 2012(Kenakin, , 2013Seifert, 2013).…”