Alternative splicing determines the post-endocytic sorting fate of G-protein-coupled receptors

Michael Tanowitz, James N Hislop, Mark von Zastrow

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 languageEnglish
Pages (from-to)35614-35621
Number of pages8
JournalThe Journal of Biological Chemistry
Volume283
Issue number51
Early online date20 Oct 2008
DOIs
Publication statusPublished - 19 Dec 2008

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Keywords

  • adenylate cyclase
  • alternative splicing
  • cell line
  • cell membrane
  • down-regulation
  • endocytosis
  • humans
  • protein isoforms
  • protein transport
  • receptors
  • opioid
  • mu

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