The roles of membrane estrogen receptor subtypes in modulating dopamine transporters in PC-12 cells

Rebecca A. Alyea, Stephanie E. Laurence, Sung H. Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Cheryl S. Watson

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

The effects of 17β-estradiol (E2) on dopamine (DA) transport could explain gender and life-stage differences in the incidence of some neurological disorders. We tested the effects of E2 at physiological concentrations on DA efflux in nerve growth factor-differentiated rat pheochromocytoma cells that express estrogen receptors (ER) α, ERβ, and G-protein coupled receptor 30 (GPR30), and DA transporter (DAT). DAT efflux was determined as the transporter-specific loss of 3H-DA from pre-loaded cells; a 9-15 min 10-9 M E2 treatment caused maximal DA efflux. Such rapid estrogenic action suggests a non-genomic response, and an E2-dendrimer conjugate (limited to non-nuclear actions) caused DA efflux within 5 min. Efflux dose-responses for E2 were non-monotonic, also characteristic of non-genomic estrogenic actions. ERα siRNA knockdown abolished E2-mediated DA efflux, while ERβ knockdown did not, and GPR30 knockdown increased E2-mediated DA efflux (suggesting GPR30 is inhibitory). Use of ER-selective agonists/antagonists demonstrated that ERα is the predominant mediator of E2-mediated DA efflux, with inhibitory contributions from GPR30 and ERβ. E2 also caused trafficking of ERα to the plasma membrane, trafficking of ERβ away from the plasma membrane, and unchanged membrane GPR30 levels. Therefore, ERα is largely responsible for non-genomic estrogenic effects on DAT activity.

Original languageEnglish (US)
Pages (from-to)1525-1533
Number of pages9
JournalJournal of neurochemistry
Volume106
Issue number4
DOIs
StatePublished - Aug 2008

Keywords

  • 17β-estradiol
  • Dopamine efflux
  • Dose-response
  • Nongenomic
  • Rapid effect

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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