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Vol. 12, Issue 12, 3797-3807, December 2001

The NH₂-terminus of Norepinephrine Transporter Contains a Basolateral Localization Signal for Epithelial Cells

Howard H. Gu,^* Xiaohong Wu,^* Bruno Giros, Marc G. Caron, Michael J. Caplan,^§ and Gary Rudnick^*

Departments of  ^*Pharmacology and  ^§Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06510; and  Department of Cell Biology and Medicine, Howard Hughes Medical Institute Laboratories, Duke University, Durham, North Carolina

When expressed in epithelial cells, dopamine transporter (DAT) was detected predominantly in the apical plasma membrane, whereas norepinephrine transporter (NET) was found in the basolateral membrane, despite 67% overall amino acid sequence identity. To identify possible localization signals responsible for this difference, DAT-NET chimeras were expressed in MDCK cells and localized by immunocytochemistry and transport assays. The results suggested that localization of these transporters in MDCK cells depends on their highly divergent NH₂-terminal regions. Deletion of the first 58 amino acids of DAT (preceding TM1) did not change its apical localization. However, the replacement of that region with corresponding sequence from NET resulted in localization of the chimeric protein to the basolateral membrane, suggesting that the NH₂-terminus of NET, which contains two dileucine motifs, contains a basolateral localization signal. Mutation of these leucines to alanines in the context of a basolaterally localized NET/DAT chimera restored transporter localization to the apical membrane, indicating that the dileucine motifs are critical to the basolateral localization signal embodied within the NET NH₂-terminal region. However, the same mutation in the context of wild-type NET did not disrupt basolateral localization, indicating the presence of additional signals in NET directing its basolateral localization within the plasma membrane.

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Corresponding author. E-mail address: gary.rudnick{at}yale.edu.

Present address: INSERM U-513, Neurobiology and Psychiatry, Faculté de Médecine de Créteil, 94000, Créteil, France.

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Molecular Biology of the Cell
Vol. 12, 3797-3807, December 2001
Copyright © 2001 by The American Society for Cell Biology

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