Lina Yao, Krista McFarland, Peidong Fan, Zhan Jiang, Yuichiro Inoue, Ivan Diamond
Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA. lina.yao@cvt.com
Proceedings of the National Academy of Sciences of the United States of America 2005 Jun 14The 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.
Lina Yao, Krista McFarland, Peidong Fan, Zhan Jiang, Yuichiro Inoue, Ivan Diamond. Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proceedings of the National Academy of Sciences of the United States of America. 2005 Jun 14;102(24):8746-51
PMID: 15937104
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