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

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Yao L, McFarland K, Fan P, Jiang Z, Inoue Y, Diamond I

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. Epub 2005 Jun 3.

PubMed ID

15937104 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Diamorphine	Mu-type opioid receptor	Protein	Humans	Yes	Agonist	Details