Dopamine, acting through D-2 receptors, inhibits rat striatal adenylate cyclase by a GTP-dependent process

This report demonstrates that the D-2 dopamine receptors that are present in rat striatum can directly inhibit the activity of adenylate cyclase in a GTP-dependent manner. N-n-propylnorapomorphine evoked a more pronounced inhibition than did dopamine. However, in the presence of the D-1-selective antagonist, SCH 23390, dopamine was also observed to inhibit the enzyme. Forskolin facilitated the detection of D-2 receptor-mediated inhibition by markedly stimulating striatal adenylate cyclase activity. The inhibition was antagonized in a dose-dependent manner by the D-2 receptor antagonist spiperone (Ki value = 70 pM) and was absolutely dependent on the presence of both GTP and sodium ions. Inhibition produced via D-2 receptors was additive with that produced via opiate or adenosine A1 receptors. The nonhydrolyzable GTP analogue, 5'-guanylylimidodiphosphate [Gpp(NH)p], did not substitute for GTP in promoting the D-2 receptor-mediated inhibition. It thus appears that D-2 receptors mediate adenylate cyclase inhibition by processes that have been observed for other neurotransmitters in the striatum and elsewhere. In addition, Gpp(NH)p displayed a Ca2+/calmodulin dependency for its inhibitory effects that was not shared by receptor-mediated, GTP-dependent inhibition.