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J. Biol. Chem., Vol. 278, Issue 24, 21576-21583, June 13, 2003

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Agonist-induced Phosphorylation of the Serotonin 5-HT_2C Receptor Regulates Its Interaction with Multiple PDZ Protein 1^*

Lisan L. Parker , Jon R. Backstrom , Elaine Sanders-Bush  and Bih-Hwa Shieh  ¶

From the Department of Medicine, and Center for Molecular and Cellular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232, Department of Pharmacology, and Center for Molecular and Cellular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Multiple PDZ domain protein 1 (MUPP1), a putative scaffolding protein containing 13 PSD-95, Dlg, ZO-1 (PDZ) domains, was identified by a yeast two-hybrid screen as a serotonin_2C receptor (5-HT_2C R)-interacting protein (Ullmer, C., Schmuck, K., Figge, A., and Lubbert, H. (1998) FEBS Lett. 424, 63–68). MUPP1 PDZ domain 10 (PDZ 10) associates with Ser⁴⁵⁸-Ser-Val at the carboxyl-terminal tail of the 5-HT_2C R. Both Ser⁴⁵⁸ and Ser⁴⁵⁹ are phosphorylated upon serotonin stimulation of the receptor (Backstrom, J. R., Price, R. D., Reasoner, D. T., and Sanders-Bush, E. (2000) J. Biol. Chem. 275, 23620–23626). To investigate whether phosphorylation of these serines in the receptor regulates MUPP1 interaction, we used several approaches. First, we substituted the serines in the receptor carboxyl tail with aspartates to mimic phosphorylation (S458D, S459D, or S458D/S459D). Pull-down assays demonstrated that Asp mutations at Ser⁴⁵⁸ significantly decreased receptor tail interaction with PDZ 10. Next, serotonin treatment of 5-HT_2C R/3T3 cells resulted in a dose-dependent reduction of receptor interaction with PDZ 10. Effects of serotonin on receptor-PDZ 10 binding could be blocked by pretreatment with a receptor antagonist. Alkaline phosphatase treatment reverses the effect of serotonin, indicating that agonist-induced phosphorylation at Ser⁴⁵⁸ resulted in a loss of MUPP1 association and also revealed a significant amount of basal phosphorylation of the receptor. We conclude that 5-HT_2C R interaction with MUPP1 is dynamically regulated by phosphorylation at Ser⁴⁵⁸.

Received for publication, October 28, 2002 , and in revised form, April 2, 2003.

^* This work was supported by National Institutes of Health (NIH) Grants EY09743 (to B.-H. S.) and MH34007 (to E. S.-B.), a grant from the National Alliance for Research on Schizophrenia and Depression (to J. R. B.), and NIGMS, NIH Minority Access to Research Careers pre-doctoral fellowship F31 GM20275 (to L. L. P.). 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.

^¶ To whom correspondence should be addressed: 402 Robinson Research Bldg., Vanderbilt University Medical Center, 23rd Ave. at Pierce, Nashville, TN 37232. Tel.: 615-343-0441; Fax: 615-343-6532; E-mail: Bih-Hwa.Shieh{at}vanderbilt.edu.

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