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J. Biol. Chem., Vol. 283, Issue 19, 12811-12818, May 9, 2008

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Glial Cell Line-derived Neurotrophic Factor Reverses Ethanol-mediated Increases in Tyrosine Hydroxylase Immunoreactivity via Altering the Activity of Heat Shock Protein 90^*

Dao-Yao He and Dorit Ron¹

From the Ernest Gallo Research Center and the Department of Neurology, University of California at San Francisco, Emeryville, California 94608

We previously found that glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA) negatively regulates alcohol drinking (He, D. Y., McGough, N. N., Ravindranathan, A., Jeanblanc, J., Logrip, M. L., Phamluong, K., Janak, P. H., and Ron, D. (2005) J. Neurosci. 25, 619–628). Several studies suggest a role for GDNF in the regulation of tyrosine hydroxylase (TH) levels in the midbrain (Georgievska, B., Kirik, D., and Bjorklund, A. (2004) J. Neurosci. 24, 6437–6445). Up-regulation of TH levels has been reported as a hallmark of biochemical adaptations to in vivo chronic exposure to drugs of abuse, including ethanol (Ortiz, J., Fitzgerald, L. W., Charlton, M., Lane, S., Trevisan, L., Guitart, X., Shoemaker, W., Duman, R. S., and Nestler, E. J. (1995) Synapse 21, 289–298). We hypothesized that GDNF plays an important role in regulating prolonged ethanol-mediated increases in TH protein levels. Using the SH-SY5Y dopaminergic-like cell line, we found that the increase in TH levels in the presence of ethanol required the activation of the cAMP/PKA pathway and was reversed by GDNF. Ethanol treatment did not alter the mRNA level or protein translation of TH, but enhanced the stability of the protein that was decreased by GDNF. Interestingly, we observed that ethanol treatment resulted in an increase in TH association with the chaperone heat shock protein (HSP90) that was mediated by the cAMP/PKA pathway and inhibited by GDNF. Taken together, these data suggest that prolonged ethanol exposure leads to increased association of TH and HSP90 via the cAMP/PKA pathway, resulting in the stabilization and subsequent accumulation of TH. GDNF reverses this ethanol-mediated adaptation by inhibiting the interaction of TH with HSP90.

Received for publication, July 27, 2007 , and in revised form, February 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 AA014366-02 (to D. R.). This work was also supported by the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (to D. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3150; Fax: 510-985-3101; E-mail: dorit.ron{at}ucsf.edu.

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