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Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization

Ying-Hui Yan1, Yan Wang1, Lan-Xue Zhao1

  • 1Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.

Neuroscience Letters
|March 11, 2014
PubMed

Insights

FK506 binding protein 12 (FKBP12) binding to the μ-opioid receptor (OPRM1) slows morphine-induced receptor internalization and desensitization, potentially contributing to morphine tolerance. This interaction impacts key signaling pathways.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • Agonist-activated μ-opioid receptor (OPRM1) signaling involves phosphorylation, β-arrestin recruitment, internalization, and desensitization.
  • Morphine, a common opioid, exhibits inefficient OPRM1 phosphorylation.
  • FK506 binding protein 12 (FKBP12) was previously shown to interact with OPRM1, attenuating phosphorylation and influencing protein kinase C activation.

Purpose of the Study:

  • To investigate the role of FKBP12-OPRM1 interaction in morphine-induced OPRM1 internalization and G protein-dependent adenylyl cyclase desensitization.
  • To explore the contribution of FKBP12's peptidyl prolyl cis-trans isomerase activity to OPRM1 phosphorylation.
  • To elucidate the potential role of FKBP12 in the development of morphine tolerance via modulation of OPRM1 trafficking.

Main Methods:

  • Utilized cell models expressing wild-type OPRM1 and a non-interacting mutant (OPRM1P353A).
  • Employed FK506 to disrupt the FKBP12-OPRM1 interaction.
  • Conducted siRNA-mediated knockdown of FKBP12.
  • Assessed receptor internalization and adenylyl cyclase desensitization kinetics.

Main Results:

  • Morphine-induced OPRM1 internalization and adenylyl cyclase desensitization were accelerated in cells lacking FKBP12 interaction (OPRM1P353A mutant or FK506 treatment).
  • Knockdown of FKBP12 using siRNA also accelerated these processes.
  • FKBP12's peptidyl prolyl cis-trans isomerase activity is implicated in inhibiting OPRM1 phosphorylation.

Conclusions:

  • FKBP12 association with OPRM1 modulates morphine-induced receptor internalization and adenylyl cyclase desensitization.
  • FKBP12 binding to OPRM1 likely inhibits receptor phosphorylation, potentially through its isomerase activity.
  • Modulation of OPRM1 trafficking by FKBP12 may contribute to the development of morphine tolerance.
Keywords:
DesensitizationFK506 binding protein 12InternalizationMorphineμ-Opioid receptor

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