TY - JOUR
T1 - Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux
AU - Alyea, Rebecca A.
AU - Watson, Cheryl S.
N1 - Funding Information:
Financial support was provided by NIEHS (T32 ES07254) and NIDA (T32 DA07287) training grants.
PY - 2009/6/16
Y1 - 2009/6/16
N2 - 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) α, β, 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 ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10-9 M E2 treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (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. Conclusion: Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.
AB - 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) α, β, 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 ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10-9 M E2 treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (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. Conclusion: Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.
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U2 - 10.1186/1471-2202-10-59
DO - 10.1186/1471-2202-10-59
M3 - Article
C2 - 19531209
AN - SCOPUS:67650511672
SN - 1471-2202
VL - 10
JO - BMC Neuroscience
JF - BMC Neuroscience
M1 - 59
ER -