Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior

Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8746-51. doi: 10.1073/pnas.0503419102. Epub 2005 Jun 3.


The nucleus accumbens (NAc) is central to heroin addiction. Activation of opiate receptors in the NAc dissociates G(i/o) into alpha and betagamma subunits. Galpha(i) inhibits cAMP production, but betagamma regulates several molecular pathways, including protein kinase A (PKA). We show in NAc/striatal neurons that opiates paradoxically activate PKA signaling by means of betagamma dimers. Activation requires Galpha(i3) and an activator of G protein signaling 3 (AGS3). AGS3 competes with betagamma for binding to Galpha(i3)-GDP and enhances the action of unbound betagamma. AGS3 and Galpha(i3) knockdown prevents opiate activation of PKA signaling. In rats self-administering heroin, AGS3 antisense in the NAc core, but not shell, eliminates reinstatement of heroin-seeking behavior, a model of human relapse. Thus, Galpha(i3)/betagamma/AGS3 appears to mediate mu opiate receptor activation of PKA signaling as well as heroin-seeking behavior.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / pathology
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • GTP-Binding Protein alpha Subunits / metabolism*
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / metabolism
  • Genetic Vectors
  • Heroin Dependence / metabolism*
  • Histological Techniques
  • Immunoprecipitation
  • Male
  • Nucleus Accumbens / metabolism*
  • Oligonucleotides
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / metabolism*
  • Signal Transduction / physiology*
  • Simplexvirus


  • Carrier Proteins
  • GTP-Binding Protein alpha Subunits
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Gpsm1 protein, rat
  • Oligonucleotides
  • Receptors, Opioid
  • Cyclic AMP-Dependent Protein Kinases