Rhes and AGS1/Dexras1 affect signaling by dopamine D1 receptors through adenylyl cyclase

The GTP binding proteins Rhes and AGS1/Dexras1 define a subfamily of the Ras superfamily and have been shown to affect signaling by G‐protein‐coupled receptors. We tested the effects of both proteins at an early stage of signaling by dopamine receptors, activation of adenylyl cyclase. Rhes decreased dopamine D1 receptor agonist‐stimulated cAMP accumulation in a pertussis toxin‐sensitive manner. It had no effect on cAMP accumulation in the absence of agonist. AGS1/Dexras1, on the other hand, decreased cAMP accumulation in both vehicle‐treated and agonist‐treated cells, resulting in a higher percentage of stimulation by agonist or a higher signal‐to‐noise ratio. The effects of AGS1/Dexras1 on cAMP accumulation were not blocked by pertussis toxin, suggesting that it may produce these effects through interaction with a Gαi monomer. Both Rhes and AGS1/Dexras1 were associated with GTP‐bound Gαi in pull‐down assays. However, Rhes had no effect on the ability of activated D2 receptor to inhibit cAMP. Neither Rhes nor AGS1/Dexras1 interacted with the D1 receptor in pull‐down assays. These findings show that, in addition to its well‐known effects on signaling through Gi‐coupled receptors, AGS1/Dexras1 can affect signaling through a Gs/olf‐coupled receptor. Furthermore, the results suggest that Rhes exerts some of its effects by interacting with Gαi. © 2011 Wiley‐Liss, Inc.