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Suppressing Drug Addiction?
Signaling through dopamine and opioid G protein–coupled receptors (GPCRs) in the brain structure called the striatum is involved in behaviors caused by drug addiction. Type 5 adenylyl cyclase (AC5) is a downstream effector of dopamine and opioid GPCRs that produces the second messenger cyclic adenosine monophosphate (cAMP). Chronic opioid treatment causes sensitization of AC5 and, upon withdrawal of opioids, leads to increased cAMP production, a phenomenon called superactivation, which may contribute to the development of opiate tolerance and dependence. The detailed biochemical and cellular analyses performed by Xie et al. revealed that a complex consisting of RGS9-2 (regulator of G protein signaling 9-2) and the G protein β subunit Gβ5 bound to and suppressed the activity of AC5 by several different mechanisms. Accordingly, stimulation of the dopamine D1 receptor produced higher cAMP concentrations in striatal membranes from mice lacking Gβ5 than those from wild-type mice. In mice undergoing acute withdrawal from chronic morphine administration, the cAMP concentration was higher in striata of RGS9 knockout mice than in those of wild-type mice. Thus, these results suggest that targeting the interaction between RGS9-2 and Gβ5 could affect the development of drug addiction.
