Abstract

Acute activation of Gα_i/o-coupled D₂ dopamine receptors inhibits A_2A adenosine receptor stimulation of adenylate cyclase. This antagonistic interaction between D₂ dopamine and A_2A adenosine receptors has been well documented; however, the effects of persistent activation of D₂ dopamine receptors on subsequent A_2A adenosine receptor signaling have not been explored. The present study investigated the effects of short-term (3-h) and long-term (18-h) activation of D_2L dopamine receptors on subsequent A_2A adenosine receptor stimulation of adenylate cyclase in CAD-D_2L and NS20Y-D_2L neuroblastoma cells. Short- and long-term activation of D_2L dopamine receptors markedly increased 5′-N-methylcarboxamidoadenosine (MECA)-stimulated cyclic AMP accumulation 1.4-fold and 1.7-fold, respectively. D_2L receptor-induced sensitization of A_2A-stimulated cyclic AMP accumulation was blocked by the D₂ antagonist spiperone and pertussis toxin pretreatment. In addition, persistent activation of A_2A adenosine receptors resulted in 50% desensitization of subsequent MECA-stimulated cyclic AMP accumulation; however, MECA-induced desensitization of A_2A adenosine receptors did not prevent completely quinpirole-induced sensitization of adenylate cyclase. These studies revealed a novel mode of regulation between D_2L dopamine and A_2A adenosine receptors and suggest a cooperative interaction in the regulation of cyclic AMP signaling.