G proteins modulate D2 receptor-coupled K(ATP) channels in rat dopaminergic terminals

The presynaptic dopamine (DA) D2 receptor-mediated regulation of ATP-sensitive potassium (K-ATP(+)) channels was examined in slices of the rat caudate-putamen. When slices were incubated with the specific D2 receptor antagonist (-)-sulpiride (SLP), a concentration-dependent increase of extracellular DA release was observed. SLP-induced enhancement was completely antagonized by coincubation with the Kc,,, channel opener diazoxide (DIA). Treatment of slices with the D2 receptor agonist quinpirole (QUI) almost completely inhibited DA outflow induced by the K-ATP(+) channel blocker butanedione-monoxime (BDM). Coincubation of SLP and guanosine triphosphate (GTP) or its non-hydrolizable analogue guanylyl-5 ' -imidodiphosphate [Gpp(NH)p], significantly reduced the SLP-induced effect on DA levels. Furthermore, we observed that BDM-induced DA outflow was markedly inhibited by G protein activators suggesting an additional receptor-independent regulation of K-ATP(+) channel gating. Our results suggest that PTX-sensitive G proteins are involved in the signal transduction between D2 receptors and K-ATP(+) channels. Furthermore, K-ATP(+) channels can be modulated in a receptor-independent mechanism by G protein activators.