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Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1)

Kyu Young Song1, Hack Sun Choi, Cheol Kyu Hwang

  • 1Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. songx047@umn.edu

Cellular and Molecular Life Sciences : CMLS
|July 18, 2009
PubMed

Insights

Researchers discovered that the OPRM1 gene

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Genetics

Background:

  • The micro opioid receptor (encoded by OPRM1) mediates the effects of morphine and related drugs.
  • Understanding OPRM1 regulation is crucial for opioid pharmacology.

Purpose of the Study:

  • To investigate how alternative translation initiation affects OPRM1 protein products.
  • To identify mechanisms controlling micro opioid receptor expression.

Main Methods:

  • Analysis of OPRM1 gene's 5'-untranslated region.
  • In vivo and in vitro translation studies.
  • Reporter and protein degradation assays.
  • Site-directed mutagenesis of OPRM1.

Main Results:

  • Differential use of a start codon in the OPRM1 5'-UTR generates distinct protein isoforms.
  • Alternative initiation at an upstream site leads to a short-lived protein via ubiquitin-proteasome degradation.
  • Mutations at specific lysine residues stabilize the alternative OPRM1 protein.
  • Upstream OPRM1 initiation reduces translation at the main AUG site.

Conclusions:

  • Alternative translation initiation is a regulatory mechanism for OPRM1.
  • The ubiquitin-proteasome pathway controls the stability of an alternatively translated OPRM1 isoform.
  • OPRM1 expression is modulated by upstream translation initiation events.

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