Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Ever since the rapid extranuclear signaling effects of 17β-estradiol (E2) were first identified in the brain decades ago, it has remained an enigma as to how these nonclassical effects are achieved. Using a forebrain-specific knockout animal model, the current study demonstrates that a recently cloned estrogen receptor coregulator protein, Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), is critical for mediating E2 regulation of rapid extranuclear signaling, as well as E2-induced neuroprotection and cognitive function in the hippocampus after ischemic injury. Our studies also identified PELP1 as a novel interacting protein and a substrate of glycogen synthase kinase-3β (GSK3β). Finally, PELP1 was also shown to mediate E2 genomic effects to regulate genes involved in inflammation, metabolism, and survival after ischemic injury.