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.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031, USA.
Nina
N
Koldzic-Zivanovic
Patricia K
PK
Seitz
Cheryl S
CS
Watson
Kathryn A
KA
Cunningham
Mary L
ML
Thomas
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