Intracellular signaling involved in estrogen regulation of serotonin reuptake.
17beta-estradiol (E2) regulates neuronal activity via genomic and rapid, non-genomic mechanisms. The rat serotonergic neuronal cell line (RN46A) was used to investigate the rapid effects of E2 on serotonin (5-HT) reuptake and on potential intracellular signaling pathways. RN46A cells express the serotonin transporter (SERT) and estrogen receptor (ER)beta, but not ERalpha. Fifteen minute E2 treatment (10(-9)M) decreased 5-HT uptake. Intracellular cAMP levels were not increased by 15 min E2 treatment; however, E2 caused an increase in intracellular Ca2+ levels, with a maximum response within the first minute. The response was E2 specific, since other steroids (17alpha-estradiol, testosterone, and progesterone) had no effect. The ER antagonist ICI 182,780 blocked the rapid E2 effects on intracellular Ca2+ levels as did the selective ER modulator tamoxifen. In summary, changes in intracellular Ca2+ levels caused by E2 and mediated through ERbeta may be responsible for observed rapid effects of E2 on SERT activity.
Koldzic-Zivanovic
Nina
N
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031, USA.
Seitz
Patricia K
PK
Watson
Cheryl S
CS
Cunningham
Kathryn A
KA
Thomas
Mary L
ML
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D005786:Gene Expression Regulation; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology
D000728:Androgens; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013629:Tamoxifen; D000077267:Fulvestrant; D012701:Serotonin; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D000242:Cyclic AMP; D002118:Calcium