Dopamine 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 Gi-coupled D2 dopamine receptors inhibits adenylyl cyclase, persistent activation enhances adenylyl cyclase activity, a phenomenon called heterologous sensitization. Previous work revealed a requirement for Gs in D2-induced heterologous sensitization of AC5. To elucidate the mechanism of Gs dependency, we expressed Gs mutants in Gs-deficient E2？/E2？ cells. Neither Gs-palmitoylation nor Gs-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 Gs-AC5 interactions in sensitization however, Gβγ appears to have an indirect role in heterologous sensitization of AC5, possibly by promoting proper signalosome assembly.