Membrane-Initiated Actions of Estrogens in Neuroendocrinology: Emerging Principles

Abstract

Hormonal ligands for the nuclear receptor superfamily have at least two interacting mechanisms of action: 1) classical transcriptional regulation of target genes (genomic mechanisms); and 2) nongenomic actions that are initiated at the cell membrane, which could impact transcription.Although transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood.Historically, this has led to a considerable divergence of thought in the molecular endocrine field.We have attempted to uncover principles of hormone action that are relevant to membrane-initiated actions of estrogens.There is evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium.Membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription.These signaling cascades may occur in parallel or in series but subsequently converge at the level of modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators.In addition, other hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription.The idea of synergistic coupling between membrane-initiated and genomic actions of hormones fundamentally revises the paradigms of cell signaling in neuroendocrinology.(Endocrine Reviews 28: 1-19, 2007) I. Introduction II.Estrogens Signal via Both Genomic and Nongenomic Modes A. The genomic mode of estrogen action B. Membrane-initiated (nongenomic) actions of estrogens: the use of membrane-limited conjugates as an experimental probe in neural cells C. Membrane-initiated (nongenomic) actions of estrogens in neural cells III.Membrane-Initiated Hormone Actions Potentiate Their Transcriptional Actions A. Coupling of the membrane-initiated actions of estrogen to transcription: the consequence for reproductive behavior B. Coupling of membrane-initiated actions of estrogens to transcription in nonreproductive functions C. The coupling of membrane-initiated actions to transcription is studied in vitro by using a two-pulse transcriptional paradigm in cell culture IV.The Signal Transduction Cascades Initiated by Estrogens at the Membrane May Occur in Parallel or in Series A. Membrane-initiated actions of estrogens may also occur in parallel or in series in the MCF-7 breast carcinoma cell line V. Convergence of the Membrane-Initiated Actions of Hormones to Transcription Involves Protein-Protein Interactions, Protein Translocation, and Protein Phosphorylation A. Coupling to transcription via stabilization or dimerization of molecules relevant to transcription B. Coupling to transcription via the physical movement of molecules into the nucleus C. Coupling to transcription via phosphorylation of molecules relevant to transcription VI.Initiation of Membrane-Initiated Actions at the Membrane Involves Both Classical "Nuclear Receptors" and Other Proteins A. The membrane estrogen receptor could be a novel protein in some cell types B. The membrane estrogen receptor is the classical ER in other cell types C. Do different cell types have different receptors?VII.Summary and Future