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J. Biol. Chem., Vol. 279, Issue 27, 28266-28275, July 2, 2004

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Par-4 Inhibits Choline Uptake by Interacting with CHT1 and Reducing Its Incorporation on the Plasma Membrane^*

Jun Xie and Qing Guo

From the Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

CHT1 is a Na⁺- and Cl^–-dependent, hemicholinium-3 (HC-3)-sensitive, high affinity choline transporter. Par-4 (prostate apoptosis response-4) is a leucine zipper protein involved in neuronal degeneration and cholinergic signaling in Alzheimer's disease. We now report that Par-4 is a negative regulator of CHT1 choline uptake activity. Transfection of neural IMR-32 cells with human CHT1 conferred Na⁺-dependent, HC-3-sensitive choline uptake that was effectively inhibited by cotransfection of Par-4. Mapping studies indicated that the C-terminal half of Par-4 was physically involved in interacting with CHT1, and the absence of Par-4·CHT1 complex formation precluded the loss of CHT1-mediated choline uptake induced by Par-4, indicating that Par-4·CHT1 complex formation is essential. Kinetic and cell-surface biotinylation assays showed that Par-4 inhibited CHT1-mediated choline uptake by reducing CHT1 expression in the plasma membrane without significantly altering the affinity of CHT1 for choline or HC-3. These results suggest that Par-4 is directly involved in regulating choline uptake by interacting with CHT1 and by reducing its incorporation on the cell surface.

Received for publication, February 11, 2004 , and in revised form, April 14, 2004.

^* This work was supported by NINDS Grant R01NS043296 from the National Institutes of Health and by grants from the Alzheimer's Association and the American Federation for Aging Research (to Q. G.). 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: Dept. of Physiology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-2226 (ext. 243); Fax: 405-271-3181; E-mail: qing-guo{at}ouhsc.edu.

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