title: Membrane-initiated steroid signaling (MISS): genomic steroid action starts at the plasma membrane.
abstract: Plasma membrane (PM) steroid recognition sites are thought to be responsible only for rapid, non-genomic responses without any link to the nuclear receptor-mediated genomic effects of steroids. We focused on a PM "glucocorticoid-importer" (GC-importer) that imports GC into rat liver cells. This site interacts also with particular gestagens (progesterone, P; medroxyprogesterone, MP; ethynodiol, Ethy) and estrogens (ethinylestradiol, EE(2); mestranol), which do not bind to the nuclear GC receptor (GR). To elucidate the role of the GC-importer, we transfected a rat wild-type hepatocyte (CC-1) and a hepatoma cell line, unable to import GC (MH 3924), with a GC<-->GR-responsive luciferase (luc)-reporter gene. Selected steroids were tested for their ability to induce or inhibit luc expression. Corticosterone (B) and dexamethasone (Dex), but also the GC-antagonists cortexolone (Cortex), P and MP, induced luc. Even the PM-impermeable BSA-derivatives of B, Dex and Cortex did so to almost the same extent as the free steroids. MH 3924 cells respond stronger than CC-1 to luc inducing steroids. Luc expression was inhibited by RU 38 486, but also by EE(2) and Ethy. The thiol reactive mesylate-derivatives of B, Dex and Cortex induced to a considerably lesser extent than the free or BSA-steroids. The thiol reagent mersalyl blocks cellular entry of GC and inhibits luc induction in CC-1 cells. Incubation with EE(2) and B of PM-vesicles, isolated from liver cells, resulted in a decrease of the density of two 75 and 52kDa G-proteins reflecting a diminished exchange of GDP by GTP.
  
  
  CONCLUSIONS
  the PM-residing GC-importer, now renamed "Steroid Hormone Recognition and Effector Complex" (SHREC) is an interdependent part of the complete GC signal propagation in which G-proteins are involved. Free SH-groups of SHREC are a prerequisite for genomic GC activity. Specific interactions between SHREC and GC-agonist/-antagonist trigger steroid-dependent signaling. However, import of the ligand into the cell terminates it. Thus, the PM-related non-genomic steroid responses are clearly linked to the GR-related genomic effects.
authors.affiliation: Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Daufeldt
authors.forename: Rainer
authors.initials: R
authors.lastname: Lanz
authors.forename: Axel
authors.initials: A
authors.lastname: Alléra
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D003350:Cortodoxone / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004970:Estrone / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000378:metabolism; D005040:Ethynodiol Diacetate / Q000031:analogs & derivatives* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008525:Medroxyprogesterone / Q000378:metabolism; D008634:Mersalyl / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D012710:Serum Albumin, Bovine; D004970:Estrone; D004997:Ethinyl Estradiol; D011374:Progesterone; D008634:Mersalyl; D005040:Ethynodiol Diacetate; D003907:Dexamethasone; C014546:ethynodiol; D008156:Luciferases; D019204:GTP-Binding Proteins; D008525:Medroxyprogesterone; D003345:Corticosterone; D003350:Cortodoxone