Membrane-initiated estrogen signaling via Gq-coupled GPCR in the central nervous system

Abstract

&NA; The last few decades have revealed increasing complexity and depth to our knowledge of receptor‐mediated estrogen signaling. Nuclear estrogen receptors (ERs) ER&agr; and ER&bgr; remain the fundamental dogma, but recent research targeting membrane‐bound ERs urges for a more expanded view on ER signaling. ER&agr; and ER&bgr; are also involved in membrane‐delineated signaling alongside membrane‐specific G protein‐coupled estrogen receptor 1 (GPER1), ER‐X, and the Gq‐coupled membrane ER (Gq‐mER). Membrane ERs are responsible for eliciting rapid responses to estrogen signaling, and their importance has been increasingly indicated in central nervous system (CNS) regulation of such functions as reproduction, energy homeostasis, and stress. While the Gq‐mER signaling pathway is well characterized, the receptor structure and gene remains uncharacterized, although it is not similar to the nuclear ER&agr;/&bgr;. This review will describe the current knowledge of this putative membrane ER and its selective ligand, STX, from its initial characterization in hypothalamic melanocortin circuitry to recent research exploring its role in the CNS outside of the hypothalamus.