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Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization

Ji Chu1, Hui Zheng, Yuhan Zhang

  • 1Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, Minnesota 55455-0217, USA. chux0086@umn.edu

Cellular Signalling
|January 2, 2010
PubMed

Insights

Morphine and DAMGO desensitize the micro-opioid receptor (MOR) differently. Morphine uses protein kinase C epsilon (PKCε) and Galphai2, leading to cross-talk with other receptors like CB1.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Micro-opioid receptor (MOR) desensitization is key to opiate tolerance.
  • Agonist-specific mechanisms underlie MOR desensitization.
  • Intracellular calcium ([Ca(2+)](i)) release is a key indicator of receptor activity.

Purpose of the Study:

  • To elucidate the distinct molecular mechanisms of MOR desensitization induced by morphine versus DAMGO.
  • To investigate the role of protein kinase C (PKC) and its subtypes in morphine-induced MOR desensitization.
  • To explore potential crosstalk between MOR and other G-protein coupled receptors.

Main Methods:

  • Monitoring of intracellular calcium ([Ca(2+)](i)) release.
  • Utilizing RNA interference and subtype-specific inhibitors to target PKC subtypes.
  • Employing site-directed mutagenesis to investigate phosphorylation sites on Galphai2.
  • Assessing desensitization of cannabinoid receptor 1 (CB1) following MOR activation.

Main Results:

  • Morphine-induced MOR desensitization is dependent on PKC, specifically PKCε.
  • DAMGO-induced desensitization does not involve PKCε.
  • Morphine-activated PKCε phosphorylates Galphai2 at specific sites (Ser44, Ser144, Ser302), impacting desensitization.
  • Morphine pre-treatment causes heterologous desensitization of CB1 receptors, suggesting crosstalk.

Conclusions:

  • Morphine and DAMGO activate distinct pathways for MOR desensitization.
  • PKCε and Galphai2 phosphorylation are critical for morphine-induced MOR desensitization.
  • MOR activation can lead to heterologous desensitization of other Gαi-coupled receptors, like CB1, via agonist-dependent mechanisms.

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