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Updated: Aug 11, 2026

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
09:39

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications

Published on: January 27, 2014

Chronic activation of ORL1 receptor induces supersensitization of adenylyl cyclase

R Y Chan1, Y H Wong

  • 1Department of Biology and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon.

Neuroreport
|November 5, 1999
PubMed

Insights

Chronic activation of the opioid receptor-like (ORL1) receptor causes cellular tolerance by inducing adenylyl cyclase (AC) supersensitization. This Gi/Go protein-mediated effect was observed in both cell lines expressing ORL1 receptors and those with endogenous ORL1 receptors.

Area of Science:

  • Pharmacology
  • Cellular Biology
  • Neuroscience

Background:

  • Opioid receptors and opioid receptor-like (ORL1) receptors share effector pathways.
  • Cellular tolerance to opioids involves adenylyl cyclase (AC) supersensitization.
  • The ORL1 receptor's role in cellular tolerance is not fully understood.

Purpose of the Study:

  • To investigate whether chronic ORL1 receptor activation induces AC supersensitization.
  • To determine the involvement of G-proteins in ORL1-mediated cellular adaptations.

Main Methods:

  • Established a HEK293 cell line stably expressing the human ORL1 receptor (293/ORL1).
  • Treated 293/ORL1 cells with nociceptin/OFQ and measured AC activity.
  • Utilized pertussis toxin to assess the role of Gi/Go proteins.
  • Examined endogenous ORL1 receptor activation in SK-N-SH neuroblastoma cells.

Main Results:

  • Chronic nociceptin/OFQ treatment of 293/ORL1 cells led to enhanced forskolin-stimulated AC activity.
  • This AC supersensitization was inhibited by pertussis toxin, implicating Gi/Go proteins.
  • Chronic activation of endogenous ORL1 receptors in SK-N-SH cells also resulted in Gi/Go-mediated AC supersensitization.

Conclusions:

  • Chronic ORL1 receptor activation induces cellular tolerance via AC supersensitization.
  • The observed AC supersensitization is mediated by Gi/Go proteins.
  • These findings highlight a conserved mechanism of cellular adaptation for both opioid and ORL1 receptors.

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