Received for publication June 5, 2004.
Revised October 14, 2004.
Accepted for publication October 15, 2004.

The composition of the beta-2 adrenergic receptor oligomer affects its membrane trafficking after ligand-induced endocytosis

Abstract

The beta-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 HEK293 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 in receptor containing the mutation, but also of the co-expressed wild type B2AR. Co-expression 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. Co-expression of the delta 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 following agonist-induced endocytosis. 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 exist 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.

Key words: Adrenergic, Receptor synthesis/trafficking, Receptor degradation, Recycling

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