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J Biol Chem, Vol. 273, Issue 40, 25616-25627, October 2, 1998
-Aminobutyric Acid Transporters GAT-2 and
GAT-3
,
From the Departments of Cellular and Molecular Physiology and
In order to perform their physiologic functions,
polarized epithelial cells must target ion transport proteins to the
appropriate domains of their plasma membranes. Molecular signals
responsible for polarized sorting have been identified for several
membrane proteins which span the bilayer once. Most ion transport
proteins are polytopic, however, and little is known of the signals
responsible for the targeting of this class of polypeptides. Members of
the Cell Biology, Yale University School of Medicine,
New Haven, Connecticut 06520
-aminobutyric acid (GABA) transporter family are polytopic
membrane proteins found endogenously in both epithelial cells and
neurons. We have identified narrowly defined sequences which are
required for the proper accumulation of two members of this transporter family in Madin-Darby canine kidney cells. The highly homologous GABA
transporter isoforms, GAT-2 and GAT-3, localize to the basolateral and
apical surfaces, respectively, when expressed stably in Madin-Darby canine kidney cells. We have generated deletion constructs and chimeric
transporters composed of complimentary portions of GAT-2 and GAT-3. We
find that information which directs their differential sorting is
present in the C-terminal cytoplasmic tails of these two polypeptides.
A sequence of 22 amino acids at the C terminus of GAT-2 is required for
the transporter's basolateral distribution and is capable of directing
GAT-3 to the basolateral surface when appended to the C terminus of
this normally apical polypeptide. The deletion of 32 amino acids from
the C terminus of GAT-3 causes this transporter to become mislocalized
to both surfaces. Moreover, removal of the final three amino acids of
GAT-3 (THF) similarly disrupts its apical sorting. The GAT-3 C-terminal
sequence resembles motifs which interact with PDZ domains, raising the
possibility that the steady state distribution of GAT-3 at the apical
plasmalemmal surface requires a protein-protein interaction mediated by
its extreme C-terminal cytoplasmic tail. These data provide the first characterization of a protein-based signal required for the apical distribution of a membrane protein.
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