Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux

BACKGROUND: Neurological diseases and neuropsychiatric disorders that vary depending on female life stages suggest that sex hormones may influence the function of neurotransmitter regulatory machinery such as the dopamine transporter (DAT). RESULTS: In this study we tested the rapid nongenomic effects of several physiological estrogens [estradiol (E(2)), estrone (E(1)), and estriol (E(3))] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12) cell model that expresses membrane estrogen receptors (ERs) α, β, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E(2)-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca(2+)-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs). Using kinase inhibitors we also showed that E(2)-mediated dopamine efflux is dependent on protein kinase C and MEK activation, but not on PI3K or protein kinase A. In plasma membrane there are ligand-independent associations of ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10(-9 )M E(2 )treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (inhibitory) away from the plasma membrane. In contrast, E(1 )and E(3 )can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane. CONCLUSION: Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.