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Could hormones explain gender differences in neurological disease?

Neurological diseases including Parkinson's, Tourette's, attention deficit hyperactivity disorder (ADHD), Alzheimer's, and schizophrenia are all associated with alterations in dopamine-driven function involving the dopamine transporter (DAT).

Research published today in the open access journal BMC Neuroscience suggests that a number of estrogens acting through their receptors affect the DAT, which may explain trends in timing of women's susceptibility to these diseases.

Rebecca Alyea and Cheryl Watson from the University of Texas Medical Branch investigated how physiological estrogen levels might influence neurochemical pathways including dopamine signalling. The authors tested the rapid nongenomic effects of several physiological estrogens (estradiol, estrone, and estriol) on dopamine efflux via the DAT in a non-transfected rat neuronal cell culture model that expresses the three membrane estrogen receptors ER¥á, ER©¬, and GPR30.

The authors found that estradiol-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca2+-mediated vesicular release of dopamine. Using kinase inhibitors they also showed that estradiol-mediated dopamine efflux is dependent on specific signaling kinases (protein kinase C and MEK, but not on PI3K or protein kinase A). While inhibiting dopamine efflux, estrone and estriol caused DAT to leave the plasma membrane.

Previous work by Alyea and Watson indicated that the suppression of efflux occurs mainly via ER¥á, and in this new study they show a physical association of ER¥á and ER©¬ with DAT before and during estrogen action, and trafficking of all three estrogen receptors in and out of the plasma membrane during dopamine efflux.

"The significance of estrogen-coupled regulation of the DAT by both direct and indirect (kinase-mediated) interactions between estrogen receptors and the DAT should provide insights into how neurological diseases which involve the DAT are related to developmental, gender, and life stage issues," says Watson. "Such regulation may suggest new ideas about treatment and prevention of diseases associated with extreme hormonal fluctuations such as in postpartum depression."

Women experience significant estrogen level changes at various life stages such as adolescence, menopause and as a result of monthly cycles. Women are also most likely to experience the onset or exacerbations of some neurological diseases at these times.

1. Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux
Rebecca A Alyea and Cheryl S Watson
BMC Neuroscience (in press)
2. BMC Neuroscience is an open access journal publishing original peer-reviewed research articles in all aspects of cellular, tissue-level, organismal, functional and developmental aspects of the nervous system. BMC Neuroscience (ISSN 1471-2202) is indexed/tracked/covered by PubMed, MEDLINE, BIOSIS, CAS, Scopus, EMBASE, PsycINFO, Thomson Reuters (ISI) and Google Scholar.

3. BioMed Central ( is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector.

Charlotte Webber | EurekAlert!
Further information:

Further reports about: BMC BioMed DAT Neuroscience STM estrogen receptor neurological disease plasma membrane

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