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The Composition of the -2 Adrenergic Receptor Oligomer Affects Its Membrane Trafficking after Ligand-Induced Endocytosis

Departments of Biochemistry and Biophysics (T.T.C.), Psychiatry (A.B., M.v.Z.), and Cellular and Molecular Pharmacology (M.v.Z.), Program in Cell Biology, University of California, San Francisco, San Francisco, California

The -2 adrenergic receptor (B2AR) is well known to form oligomeric complexes in vivo, but the functional significance of this process is not fully understood. The present results identify an effect of oligomerization of the human B2AR on the membrane trafficking of receptors after agonist-induced endocytosis in stably transfected human embryonic kidney 293 cells. A sequence present in the cytoplasmic tail of the B2AR has been shown previously to be required for efficient recycling of internalized receptors. Mutation of this sequence was observed to inhibit recycling not only of the receptor containing the mutation but also of the coexpressed wild-type B2AR. Coexpression of recycling-defective mutant B2ARs also enhanced proteolytic degradation of the wild-type B2AR after agonist-induced endocytosis, consistent with trafficking of both receptors to lysosomes in an oligomeric complex. Coexpression of the opioid receptor (DOR) at similar levels produced a much smaller effect on endocytic trafficking of the B2AR, even though DOR traverses a similar membrane pathway as recycling-defective mutant B2ARs. Biochemical studies confirmed that B2AR/B2AR-ala homomeric complexes form more readily than DOR/B2AR heteromers in expression-matched cell clones and support the hypothesis that B2AR/B2AR-ala complexes are not disrupted by agonist. These results suggest that a significant fraction of B2ARs exists in oligomeric complexes after ligand-induced endocytosis and that the composition of the oligomeric complex influences the sorting of endocytosed receptors between functionally distinct recycling and degradative membrane pathways.

Address correspondence to: Dr. Mark von Zastrow, Genentech Hall, Rm N212E, 600 16th St., University of California, San Francisco, San Francisco, CA 94143-2140. E-mail zastrow{at}itsa.ucsf.edu

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