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The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism

James D Robinson1, Patricia H McDonald1

  • 1Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.

Cellular Signalling
|April 11, 2015
PubMed

Insights

Orexin 1 receptor (OX1R) signaling modulates kappa opioid receptor (KOR) function, favoring β-arrestin/p38 pathways over Gαi signaling. This unidirectional crosstalk may impact KOR

Area of Science:

  • Neuropharmacology
  • GPCR signaling

Background:

  • Orexin 1 receptor (OX1R) and kappa opioid receptor (KOR) are G protein-coupled receptors (GPCRs) involved in drug reward.
  • Understanding receptor-receptor interactions is crucial for elucidating complex signaling pathways.

Purpose of the Study:

  • To investigate the functional crosstalk between OX1R and KOR.
  • To determine if OX1R activation modulates KOR signaling and vice versa.

Main Methods:

  • Heterologous expression of OX1R and KOR in cells.
  • Assays for cAMP inhibition, β-arrestin recruitment, and p38 activation.
  • Assessment of OX1R internalization and ligand binding.
  • Use of JNK inhibitor SP-600125.

Main Results:

  • OX1R activation attenuated KOR-mediated cAMP inhibition but enhanced β-arrestin recruitment and p38 activation.
  • These effects were JNK-dependent and independent of OX1R internalization or KOR ligand binding.
  • KOR activation did not affect OX1R Gαq coupling, indicating unidirectional crosstalk.

Conclusions:

  • OX1R signaling unidirectionally modulates KOR function via a JNK-dependent mechanism.
  • This modulation shifts KOR signaling preference towards β-arrestin/p38 pathways.
  • This crosstalk has potential implications for the behavioral effects of KOR activity.
Keywords:
CrosstalkDynorphinGPCRJNKOrexin

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