Nongenomic steroidal modulation of high-affinity serotonin transport

Biochim Biophys Acta. 1999 Feb 4;1417(1):157-66. doi: 10.1016/s0005-2736(98)00255-7.


The ability of steroids to modulate high-affinity 5-HT transport was investigated using cell-based models which stably manifest all known properties of this transport system. beta-Estradiol (E2) exhibited noncompetitive, and possibly allosteric, inhibition of both radiolabeled serotonin ([3H]5-HT) transport by, and radiolabeled cocaine congener ([3H]CFT) binding to, this system. Such inhibitory effects were observed within short time courses and unlikely to result from genomic effects normally ascribed to estrogen action. Rather, such nongenomic effects on 5-HT uptake were more akin to modulatory effects of select steroid metabolites on other plasma membrane systems such as neurotransmitter receptors and ionic channels. Beyond E2, preliminary examination of other steroid metabolites and synthetic steroid receptor agonists/antagonists revealed that inhibition of 5-HT transport is additionally attributable only to estriol (E3, an E2 metabolite) and tamoxifen (a nonsteroidal, E2 receptor antagonist). These findings indicate that the present form of transport modulation is only rendered by select compounds and not a general property of steroidal and related agents. Assessments of covalent conjugates of E2 suggested that E2 interacts with the transporter protein at allosteric site(s) inaccessible from the extracellular domain. These findings collectively suggest that steroid-mediated regulation of 5-HT transport may be a physiologically relevant mechanism, and that antidepressant as well as psychostimulant effects in vivo may contain a steroidal component.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / chemistry
  • Carrier Proteins / drug effects*
  • Cell Line
  • Cocaine / analogs & derivatives
  • Cocaine / metabolism
  • Cocaine / pharmacology
  • Dose-Response Relationship, Drug
  • Estradiol / pharmacology*
  • Humans
  • Ion Channels / drug effects
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / drug effects*
  • Membrane Transport Proteins*
  • Mice
  • Nerve Tissue Proteins*
  • Receptors, Neurotransmitter / drug effects
  • Serotonin / metabolism*
  • Serotonin / pharmacology
  • Serotonin Plasma Membrane Transport Proteins
  • Tamoxifen / pharmacology
  • Time Factors


  • Carrier Proteins
  • Ion Channels
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Neurotransmitter
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Tamoxifen
  • Serotonin
  • Estradiol
  • (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
  • Cocaine

Associated data

  • GENBANK/AF013604