Abstract
Mu-type opioid receptors are physiologically important G-protein-coupled receptors that are generally thought to recycle after agonist-induced endocytosis. Here we show that several alternatively spliced receptor variants fail to do so efficiently because of splice-mediated removal of an endocytic sorting sequence that is present specifically in the MOR1 variant. All of the recycling-impaired receptor variants were found to undergo proteolytic down-regulation more rapidly than MOR1, irrespective of moderate differences in endocytic rate, indicating that alternative splicing plays a specific role in distinguishing the trafficking itinerary of receptors after endocytosis. The recycling-impaired MOR1B variant was similar to MOR1 in its ability to mediate opioid-dependent inhibition of adenylyl cyclase, and to undergo opioid-induced desensitization in intact cells. Functional recovery (resensitization) of MOR1B-mediated cellular responsiveness after opioid removal, however, was significantly impaired (4-fold reduction in rate) compared with MOR1. To our knowledge the present results are the first to establish a role of alternative RNA processing in specifying the post-endocytic sorting of G-protein-coupled receptors between divergent and functionally distinct membrane pathways.
Original language | English |
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Pages (from-to) | 35614-35621 |
Number of pages | 8 |
Journal | The Journal of Biological Chemistry |
Volume | 283 |
Issue number | 51 |
Early online date | 20 Oct 2008 |
DOIs | |
Publication status | Published - 19 Dec 2008 |
Keywords
- adenylate cyclase
- alternative splicing
- cell line
- cell membrane
- down-regulation
- endocytosis
- humans
- protein isoforms
- protein transport
- receptors
- opioid
- mu