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The Journal of Neuroscience, August 15, 2002, 22(16):7045-7054

The Multiple LIM Domain-Containing Adaptor Protein Hic-5 Synaptically Colocalizes and Interacts with the Dopamine Transporter

Ana M. Carneiro^{1, 2}, Susan L. Ingram³, Jean-Martin Beaulieu¹, Ava Sweeney¹, Susan G. Amara³, Sheila M. Thomas⁴, Marc G. Caron¹, and Gonzalo E. Torres¹

¹ Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, ² Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais Belo Horizonte, Brazil, ³ Howard Hughes Medical Institute, Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, and ⁴ Cancer Biology Program, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts 02215

The Na⁺/Cl-dependent dopamine transporter (DAT) is critical in terminating dopaminergic transmission by removing the transmitter away from the synapse. Several lines of evidence suggest that transporter-interacting proteins may play a role in DAT function and regulation. In this report, using the yeast two-hybrid system, we have identified a novel interaction between DAT and the multiple Lin-11, Isl-1, and Mec-3 (LIM) domain-containing adaptor protein Hic-5. This association involves the N-terminal portion of the intracellular tail of DAT and the LIM region of Hic-5. In human embryonic kidney 293 cells, Hic-5 colocalizes with DAT at polarized sites and reduces DAT uptake activity through a mechanism involving a decrease in the cell-surface levels of the transporter. A fragment of Hic-5 containing the LIM domains is sufficient to bind DAT but lacks the ability to inhibit transporter activity. In addition, the LIM fragment prevents the effect of the full-length Hic-5 on DAT localization and function. In the brain, Hic-5 protein is expressed in the cerebral cortex, hippocampus, hypothalamus, cerebellum, and striatum, suggesting a role for this protein in the nervous system. The association of the endogenous Hic-5 and DAT proteins was confirmed biochemically by coimmunoprecipitation from brain striatal extracts. Moreover, immunostaining of rat midbrain neurons in culture revealed a presynaptic colocalization of Hic-5 and DAT. Because Hic-5 has been shown to interact with several signaling molecules, including the nonreceptor protein tyrosine kinases focal adhesion kinase and Fyn, this raises the possibility that this adaptor protein may link DAT to intracellular signaling pathways.

Key words: dopamine transporter; Hic-5; adaptor; interaction; colocalization; uptake; LIM domain

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22167045-10$05.00/0

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