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 (E2), estrone (E1), and estriol (E3)] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12) cell model that expresses membrane estrogen receptors (ERs) alpha, beta, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E2-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca2+-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs). Using kinase inhibitors we also showed that E2-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 ERalpha and ERbeta (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10(-9) M E2 treatment) cause trafficking of ERalpha (stimulatory) to the plasma membrane and trafficking of ERbeta (inhibitory) away from the plasma membrane. In contrast, E1 and E3 can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane.


CONCLUSIONS
Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.
Alyea
Rebecca A
RA
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0645, USA. raalyea@mail.utexas.edu
Watson
Cheryl S
CS
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000145:classification / Q000378:metabolism* / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000145:classification / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D004967:Estrogens; C520305:Gper1 protein, rat; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D014316:Tritium; D012110:Reserpine; D020932:Nerve Growth Factor; D002118:Calcium; D004298:Dopamine