title: cGMP-dependent ADP depolymerization of actin mediates estrogen increase in cervical epithelial permeability.
abstract: Estrogen increases secretion of cervical mucus in women, and the effect depends on fragmentation of the cytoskeleton. The objective of the present study was to understand the molecular mechanism of estrogen action. Treatment of human cervical epithelial cells with 17beta-estradiol, sodium nitroprusside (SNP), or 8-bromoguanosine 3', 5'-cyclic monophosphate (8-Br-cGMP) increased cellular monomeric G-actin and decreased polymerized F-actin. The effects of estradiol were blocked by tamoxifen, by the guanylate cyclase inhibitor LY-83583, and by the cGMP-dependent protein kinase inhibitor KT-5823. The effects of SNP were blocked by LY-83583 and KT-5823, while the effects of 8-Br-cGMP were blocked only by KT-5823. Treatment with phalloidin decreased paracellular permeability and G-actin. Treatment with 17beta-estradiol, SNP, or 8-Br-cGMP attenuated SNP-induced phosphorylation of [(32)P]adenylate NAD in vitro: tamoxifen blocked the effect of estrogen; LY-83583 blocked the effect of SNP but not that of 8-Br-cGMP, while KT-5823 blocked effects of both SNP and 8-Br-cGMP. These results indicate that estrogen, nitric oxide (NO), and cGMP stimulate actin depolymerization. A possible mechanism is NO-induced, cGMP-dependent protein kinase augmentation of ADP-ribosylation of monomeric actin.
authors.affiliation: Departments of Reproductive Biology and Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. gig@po.cwru.edu
authors.forename: G I
authors.initials: GI
authors.lastname: Gorodeski
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000199:Actins / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D002227:Carbazoles; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002582:Cervix Mucus / Q000378:metabolism; D002584:Cervix Uteri / Q000166:cytology; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism; D012266:Ribose / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000199:Actins; D000470:Alkaloids; D000634:Aminoquinolines; D002227:Carbazoles; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D007211:Indoles; D011108:Polymers; D014665:Vasodilator Agents; D013629:Tamoxifen; C073601:KT 5823; D009599:Nitroprusside; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide; D004958:Estradiol; D000244:Adenosine Diphosphate; D012266:Ribose; C041715:6-anilino-5,8-quinolinedione; D006152:Cyclic GMP