Membrane-Initiated Actions of Estrogens in Neuroendocrinology: Emerging Principles
Nandini Vasudevan and
Donald W. Pfaff
Department of Biology (N.V.), Pennsylvania State University, University Park, Pennsylvania 16802; and Laboratory of Neurobiology and Behavior (D.W.P.), The Rockefeller University, New York, New York 10021
Correspondence: Address all correspondence and requests for reprints to: Dr. Nandini Vasudevan, 208 Mueller Laboratory, Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802. E-mail: nuv1{at}psu.edu
Hormonal ligands for the nuclear receptor superfamily have atleast two interacting mechanisms of action: 1) classical transcriptionalregulation of target genes (genomic mechanisms); and 2) nongenomicactions that are initiated at the cell membrane, which couldimpact transcription. Although transcriptional mechanisms areincreasingly well understood, membrane-initiated actions ofthese ligands are incompletely understood. Historically, thishas led to a considerable divergence of thought in the molecularendocrine field.
We have attempted to uncover principles of hormone action thatare relevant to membrane-initiated actions of estrogens. Thereis evidence that the membrane-limited actions of hormones, particularlyestrogens, involve the rapid activation of kinases and the releaseof calcium. Membrane actions of estrogens, which activate theserapid signaling cascades, can also potentiate nuclear transcription.These signaling cascades may occur in parallel or in seriesbut subsequently converge at the level of modification of transcriptionallyrelevant molecules such as nuclear receptors and/or coactivators.In addition, other hormones or neurotransmitters may also activatecascades to crosstalk with estrogen receptor-mediated transcription.The idea of synergistic coupling between membrane-initiatedand genomic actions of hormones fundamentally revises the paradigmsof cell signaling in neuroendocrinology.
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