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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.
Carneiro1, 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
Copyright © 2002 Society for Neuroscience 0270-6474/02/22167045-10$05.00/0
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