Abstract
Chronic dopamine receptor activation is implicated in several central nervous system disorders. Although acute activation of Gα i-coupled D2 dopamine receptors inhibits adenylyl cyclase, persistent activation enhances adenylyl cyclase activity, a phenomenon called heterologous sensitization. Previous work revealed a requirement for Gα s in D2-induced heterologous sensitization of AC5. To elucidate the mechanism of Gα s dependency, we expressed Gα s mutants in Gα s-deficient Gnas E2−/E2− cells. Neither Gα s-palmitoylation nor Gα s-Gβγ interactions were required for sensitization of AC5. Moreover, we found that coexpressing βARKct-CD8 or Sar1(H79G) blocked heterologous sensitization. These studies are consistent with a role for Gα s-AC5 interactions in sensitization however, Gβγ appears to have an indirect role in heterologous sensitization of AC5, possibly by promoting proper signalosome assembly.
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