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J Biol Chem, Vol. 273, Issue 37, 24196-24206, September 11, 1998

Targeting of G Protein-coupled Receptors to the Basolateral Surface of Polarized Renal Epithelial Cells Involves Multiple, Non-contiguous Structural Signals

From the Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600

Truncations and chimeras of the _2A-adrenergic receptor (_2AAR) were evaluated to identify membrane domains responsible for its direct basolateral targeting in Madin-Darby canine kidney cells. An _2AAR truncation, encoding transmembrane (TM) regions 1-5, was first delivered basolaterally, but within minutes appeared apically, and at steady-state was primarily lateral in its immunocytochemical localization. A TM 1-5 truncation with the third intracellular loop revealed more intense lateral localization than for the TM 1-5 structure, consistent with the role of the third intracellular loop in _2AAR stabilization. Addition of TM 6-7 of A₁ adenosine receptor (A₁AdoR) to _2AARTM1-5 creates a chimera, _2AARTM1-5/A₁AdoRTM6-7, which was first delivered apically, resulting either from loss of _2AAR sorting information in TM 6-7 or acquisition of apical trafficking signals within A₁AdoRTM6-7. Evidence that _2AARTM6-7 imparts basolateral targeting information is revealed by the significant basolateral localization of the A₁AdoRTM1-5/_2AARTM6-7 and A₁AdoRTM1-5/_2AARTM6-7+i3 chimeras, in contrast to the dominant apical localization of A₁AdoR. These results reveal that sequences within TM 1-5 and within TM 6-7 of the _2AAR confer basolateral targeting, providing the first evidence that _2AAR basolateral localization is not conferred by a single region but by non-contiguous membrane-embedded or proximal sequences.

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