Perspectives in Pharmacology Steroid Hormone Interactions with Target Cells: Cross Talk between Membrane and Nuclear Pathways

The biological effects of steroid hormones are mediated by receptors associated with the plasma membrane as well as located inside of target cells. This perspective focuses on recent advances in our understanding of the integration that occurs between membrane-associated rapid signaling events and various changes in gene transcription that modulate the function and phenotype of steroid-responsive cells. Three frequently studied members of the steroid hormone receptor superfamily, the estrogen receptors, the thyroid hormone receptors, and the vitamin D receptors, are included to illustrate the emerging concepts. Each of these hormones has been conclusively shown to function at multiple subcellular sites leading to a continuum of signals intimately linked by intracellular cross talk. Understanding the molecular mechanisms by which these steroid hormones and their receptors transduce cellular signals will allow us to create new pharmacologic therapies aimed at treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others. We have entered a new era in understanding the mechanisms by which steroid hormones exert their effects on target cells. This era is characterized by increased appreciation for the interacting network of responses that begin immediately upon exposure of cells to steroid and culminate in changes in gene expression affecting function and phenotype. Understanding this continuum of change, including the potential for cross talk with other pathways and the elaborate feedback mechanisms that are activated, provides unprecedented opportunity to develop novel therapeutics that direct specific responses of target cells. As a scientific community, we have moved past the arguments concerning whether membrane, cytoplasmic, or nuclear receptor-mediated pathways take precedence, and on to an era in which we are challenged to understand the complexities of steroid hormones as key integrators of cellular function. Confusion persists in the literature, much of which has accumulated from inconsistent vocabulary usage in scientific publications. In this perspective, we use terminology defined below. “Genomic” refers to any action of a hormone that leads to a change in gene transcription, regardless of whether the classical nuclear receptor for that steroid hormone is involved. “Nongenomic” is used for changes that occur in presynthesized cellular machinery that occur independently of new messenger RNA transcription. This term should not be used when referring to rapid changes that clearly initiate new transcription. “Nuclear receptor-mediated” refers to changes that require direct or indirect actions of the classical The work in our laboratories was supported by grants from the National Institutes of Health/National Institute of Dental and Craniofacial Research (M.C.F.-C.) and from the Department of Veterans Affairs (P.J.D.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.055038. ABBREVIATIONS: ER, estrogen receptor; TR, thyroid hormone receptor; VDR, vitamin D receptor; nER, nuclear ER; ERE, estrogen response element; KO, knockout; SRCs, steroid receptor coactivators; SERM, selective estrogen receptor modulator; LBD, ligand-binding domain; mER, membrane ER; PI3K, phosphatidylinositol 3-phosphate kinase; PKC, protein kinase C; TH, thyroid hormone; TR, TH receptor; RXR, retinoic acid receptor; T3, 3,5,3 -triiodo-L-thyronine; TRE, TH response element; SMRT, silencing mediator of TH and retinoid action; NCoR, nuclear corepressor; T4, L-thyroxine; DBD, DNA-binding domain; SR, sarcoplasmic reticulum; STAT, signal transducer and activator of transcription; VDRE, vitamin D response elements; mVDR, membrane receptors for 1,25(OH)2D3; 1,25D3-MARRS, membrane-associated rapid response to steroids; TGF , transforming growth factor ; MAPK, mitogen-activated protein kinase; eNOS, endothelial nitric-oxide synthase; [Ca ]i, intracellular calcium concentration. 0022-3565/03/3073-839–845$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 307, No. 3 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 55038/1103683 JPET 307:839–845, 2003 Printed in U.S.A. 839 at A PE T Jornals on M ay 1, 2017 jpet.asjournals.org D ow nladed from nuclear steroid hormone receptors. “Post-transcriptional” defines changes requiring new protein translation or to ribosomal activation without new gene transcription. “Posttranslational” protein modifications include changes in the glycosylation state, lipid addition, and phosphorylation. “Rapid” refers to any action that takes place on a time scale from milliseconds to minutes. “Long term” includes effects that occur many hours or even days after hormone addition. “Intermediate” includes those events occurring within a few hours and not necessarily persisting for a day, comprising many of the actions involved in cross talk between genomic and nongenomic responses. “Membrane-initiated” is limited to use when the effect of the steroid clearly involves changes in membrane protein activity such as occurs with surface receptors, ion channels, or membrane-associated signaling complexes. This term also is appropriately used when referring to changes in membrane lipids such as changes in fluidity or to lipid hydrolysis. This perspective emphasizes steroid effects on signaling pathways, new mechanisms of cross talk in target cells, and potential and required receptors that may represent pharmacological targets. We chose three diverse steroid hormone receptor family members, estrogen receptors (ER), thyroid hormone receptors (TR), and vitamin D receptors (VDR), to explain the emerging concepts, but note that these concepts apply to other steroid hormone receptor superfamily members.