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J. Biol. Chem., Vol. 283, Issue 19, 13216-13224, May 9, 2008

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A Regulatory Domain in the N Terminus of Tryptophan Hydroxylase 2 Controls Enzyme Expression^*

Karen L. Murphy¹, Xiaodong Zhang², Raul R. Gainetdinov, Jean-Martin Beaulieu³, and Marc G. Caron, NARSAD Lattner Foundation Distinguished Investigator⁴

From the Departments of Neurobiology and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Serotonin is involved in a variety of physiological processes in the central nervous system and the periphery. As the rate-limiting enzyme in serotonin synthesis, tryptophan hydroxylase plays an important role in modulating these processes. Of the two variants of tryptophan hydroxylase, tryptophan hydroxylase 2 (TPH2) is expressed predominantly in the central nervous system, whereas tryptophan hydroxylase 1 (TPH1) is expressed mostly in peripheral tissues. Although the two enzymes share considerable sequence homology, the regulatory domain of TPH2 contains an additional 41 amino acids at the N terminus that TPH1 lacks. Here we show that the extended TPH2 N-terminal domain contains a unique sequence involved in the regulation of enzyme expression. When expressed in cultured mammalian cells, TPH2 is synthesized less efficiently and is also less stable than TPH1. Removal of the unique portion of the N terminus of TPH2 results in expression of the enzyme at a level similar to that of TPH1, whereas protein chimeras containing this fragment are expressed at lower levels than their wild-type counterparts. We identify a region centered on amino acids 10–20 that mediates the bulk of this effect. We also demonstrate that phosphorylation of serine 19, a protein kinase A consensus site located in this N-terminal domain, results in increased TPH2 stability and consequent increases in enzyme output in cell culture systems. Because this domain is unique to TPH2, these data provide evidence for selective regulation of brain serotonin synthesis.

Received for publication, August 14, 2007 , and in revised form, March 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants MH-40159 and MH-79201 (to M. G. C.). This work was also supported by a grant from the Lennon Family Foundation. 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 Recipient of a predoctoral fellowship from the Howard Hughes Medical Institute.

² Supported by an NARSAD Young Investigator Award. Present address: Duke-NUS Graduate Medical School Singapore, 2 Jalan Bukit Merah, Singapore 169547.

³ NARSAD Young Investigator and recipient of a fellowship from the Canadian Institutes of Health Research. Present address: Dept. of Physiology and Anatomy, CRULRG Université Laval, Quebec City, Quebec G1J 2G3, Canada.

⁴ To whom correspondence should be addressed: Dept. of Cell Biology, Box 3287, Duke University Medical Center, 487 CARL Bldg., Research Dr., Durham, NC 27710. Tel.: 919-684-5433; Fax: 919-681-8641; E-mail: m.caron{at}cellbio.duke.edu.

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