Dopamine D(2) Receptor-Mediated Heterologous Sensitization of AC5 Requires Signalosome Assembly

Chronic dopamine receptor activation is implicated in several central nervous system disorders. Although acute activation of Gα (i)-coupled D(2) 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 D(2)-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.