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

TLDR

The study proposes that the estrogen receptor activating the MAPK cascade in the developing brain is a novel, plasma‑membrane‑associated receptor distinct from ER‑α and ER‑β. This putative receptor, termed ER‑X, is localized to caveolar‑like microdomains in postnatal cortical and uterine plasma membranes and is re‑expressed in adult brain after ischemic injury. Experimental data demonstrate that ER‑X is a high‑affinity, saturable estradiol binding site (~1.6 nm) distinct from ER‑α/β, re‑expressed after stroke, and capable of rapidly activating MAPK signaling.

Abstract

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 (<i>K</i>_d, ∼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.