Identification and Characterization of Three New Alternatively Spliced μ-Opioid Receptor Isoforms

  1. Ying-Xian Pan,
  2. Jin Xu,
  3. Elizabeth Bolan,
  4. Catherine Abbadie,
  5. Albert Chang,
  6. Amy Zuckerman,
  7. Grace Rossi and
  8. Gavril W. Pasternak
  1. The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York

    Abstract

    We have identified four new μ-opiod receptor (MOR)-1 exons, indicating that the gene now contains at least nine exons spanning more than 200 kilobases. Replacement of exon 4 by combinations of the new exons yields three new receptors. When expressed in Chinese hamster ovary cells, all three variants displayed high affinity for μ-opioid ligands, but κ and δ drugs were inactive. However, there were subtle, but significant, differences in the binding profiles of the three variants among themselves and from MOR-1. Immunohistochemically, the major variant, MOR-1C, displayed a regional distribution quite distinct from that of MOR-1. Region-specific processing also was seen at the mRNA level. Antisense mapping revealed that the four new exons were all involved in morphine analgesia. Together with two other variants generated from alternative splicing of exon 4, there are now six distinct MOR-1 receptors.

    Footnotes

    • Send reprint requests to: Dr. Gavril W. Pasternak, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. E-mail:pasterng{at}mskmail.mskcc.org

    • This work was supported in part by the National Institute on Drug Abuse Grants DA02615, DA06241, and DA07242; Senior Scientist Award DA00220 (to G.W.P.) and Research Scientist Development Award DA00296 (to Y.-X.P.); and Core Grant CA08748 (to the Memorial Sloan-Kettering Cancer Center).

    • Abbreviations:
      MOR
      μ-opioid receptor
      DAMGO
      [d-Ala2,N-MePhe4,Gly-ol5]enkephalin
      M6G
      morphine-6β-glucuronide
      RT
      reverse transcription
      PCR
      polymerase chain reaction
      FISH
      fluorescence in situ hybridization
      BAC
      bacterial artificial chromosome
      • Received February 3, 1999.
      • Accepted April 13, 1999.
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    1. Molecular Pharmacology August 1, 1999 vol. 56 no. 2 396-403
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