Dopamine D2 Receptor-Mediated Heterologous Sensitization of AC5 Requires Signalosome Assembly

Abstract EN

Chronic dopamine receptor activation is implicated in several central nervous system disorders.

Although acute activation of Gαi-coupled D2 dopamine receptors inhibits adenylyl cyclase, persistent activation enhances adenylyl cyclase activity, a phenomenon called heterologous sensitization.

Previous work revealed a requirement for Gαs in D2-induced heterologous sensitization of AC5.

To elucidate the mechanism of Gαs dependency, we expressed Gαs mutants in Gαs-deficient GnasE2−/E2− cells.

Neither Gαs-palmitoylation nor Gαs-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 Gαs-AC5 interactions in sensitization however, Gβγ appears to have an indirect role in heterologous sensitization of AC5, possibly by promoting proper signalosome assembly.