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

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Gbetagamma that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein

Hoau-Yan Wang1, Lindsay H Burns

  • 1Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, New York 10031, USA. hywang@sci.ccny.cuny.edu

Journal of Neurobiology
|September 13, 2006
PubMed

Insights

Chronic morphine alters mu opioid receptor (MOR) signaling, switching from Gi/o to Gs proteins. This switch, involving Gbetagamma subunits, contributes to morphine tolerance and dependence.

Area of Science:

  • Neuropharmacology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Chronic morphine administration alters mu opioid receptor (MOR) G protein coupling from Gi/o to Gs.
  • This signaling shift is linked to excitatory cellular effects, morphine tolerance, and dependence.
  • Ultra-low-dose naloxone can attenuate these morphine-induced signaling and behavioral changes.

Purpose of the Study:

  • To investigate the specific Gbeta isotypes involved in MOR G protein coupling after chronic morphine treatment.
  • To compare the Gbeta isotypes within Gs and Go heterotrimers coupled to MOR with those interacting with adenylyl cyclase II and IV.
  • To elucidate the mechanism by which MOR signaling shifts to Gs and its role in morphine's effects.

Main Methods:

  • Utilizing striatal tissue from rats subjected to chronic morphine treatment.
  • Employing G protein isotyping techniques to identify Gbeta subunits.
  • Analyzing the interaction of Gbetagamma subunits with adenylyl cyclase types II and IV.

Main Results:

  • Chronic morphine treatment causes a Gs heterotrimer associated with MOR to release its Gbetagamma subunit.
  • This released Gbetagamma subunit subsequently interacts with adenylyl cyclase.
  • The study identified specific Gbeta isotypes involved in these altered signaling pathways.

Conclusions:

  • The switch in MOR coupling to Gs proteins in response to chronic morphine involves the release of Gbetagamma subunits.
  • This released Gbetagamma interacts with adenylyl cyclase, contributing to a dual activation pathway.
  • These findings suggest a novel mechanism for MOR signaling that underlies morphine tolerance and dependence, which can be modulated by ultra-low-dose naloxone.

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