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We showed previously in neocortical explants, derived from developing wild-type and estrogen receptor (ER)-α gene-disrupted (ERKO) mice, that both 17α- and 17β-estradiol elicit the rapid and sustained phosphorylation and activation of the mitogen-activated protein kinase (MAPK) isoforms, the extracellular signal-regulated kinases ERK1 and ERK2. We proposed that the ER mediating activation of the MAPK cascade, a signaling pathway important for cell division, neuronal differentiation, and neuronal survival in the developing brain, is neither ER-α nor ER-β but a novel, plasma membrane-associated, putative ER with unique properties. The data presented here provide further evidence that points strongly to the existence of a high-affinity, saturable, 3H-estradiol binding site (Kd, ∼1.6 nm) in the plasma membrane. Unlike neocortical ER-α, which is intranuclear and developmentally regulated, and neocortical ER-β, which is intranuclear and expressed throughout life, this functional, plasma membrane-associated ER, which we have designated “ER-X,” is enriched in caveolar-like microdomains (CLMs) of postnatal, but not adult, wild-type and ERKO neocortical and uterine plasma membranes. We show further that ER-X is functionally distinct from ER-α and ER-β, and that, like ER-α, it is re-expressed in the adult brain, after ischemic stroke injury. We also confirmed in a cell-free system that ER-α is an inhibitory regulator of ERK activation, as we showed previously in neocortical cultures. Association with CLM complexes positions ER-X uniquely to interact rapidly with kinases of the MAPK cascade and other signaling pathways, providing a novel mechanism for mediation of the influences of estrogen on neuronal differentiation, survival, and plasticity.

ER-X: A Novel, Plasma Membrane-Associated, Putative Estrogen Receptor That Is Regulated during Development and after Ischemic Brain Injury