Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior.
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.
Yao
Lina
L
Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA. lina.yao@cvt.com
McFarland
Krista
K
Fan
Peidong
P
Jiang
Zhan
Z
Inoue
Yuichiro
Y
Diamond
Ivan
I
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D005822:Genetic Vectors; D006556:Heroin Dependence / Q000378:metabolism*; D006652:Histological Techniques; D047468:Immunoprecipitation; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D009841:Oligonucleotides; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018139:Simplexvirus
D002352:Carrier Proteins; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C498913:Gpsm1 protein, rat; D009841:Oligonucleotides; D011957:Receptors, Opioid; D017868:Cyclic AMP-Dependent Protein Kinases